jCells are similar to stem cells that haven’t yet fully developed into mature photoreceptors. The cells are injected into the vitreous, the soft, gel-like substance in the middle of the eye. Intravitreal injections have a good record of safety and are commonly administered for other conditions in a doctor’s office. jCells are designed to release proteins known as neurotrophic factors to preserve photoreceptors regardless of the mutated gene causing vision loss.
Previously, the company reported on 76 patients in the Phase 2b trial for jCells. In the Phase 2b trial, 39 percent of patients receiving 6 million cells, the high dose of the treatment, had improvement at 12 months post-treatment in best corrected visual acuity (BCVA) of 10 letters (two lines on an eye chart) or more, with 26 percent improving by at least 15 letters. In the sham group, 19 percent and 8 percent had BCVA improvement of 10 or more and 15 or more letters, respectively. Substantial improvements for eyes treated with 6 million jCells as compared to sham were also seen in contrast sensitivity, kinetic visual fields, and mobility-related visual function (as captured by the VFQ-48 questionnaire). The 3 million cell dose, the lower dose of treatment included in the study, was shown to be inferior to the 6 million cell dose.
]]>Beacon Therapeutics has reported vision improvements for five of eight patients receiving the high dose of its X-linked retinitis pigmentosa (XLRP) gene therapy in the Phase 2 SKYLINE clinical trial. Known as AGTC-501, the emerging gene therapy is for patients with mutations in RPGR, the gene most frequently associated with XLRP. Interim, 12-month results for SKYLINE were reported on February 7, 2024, by Mark Pennesi, MD, PhD, director, Ophthalmic Genetics at the Retina Foundation of the Southwest, at the 47th Macula Society Meeting.
Vision improvements were measured using microperimetry, a test that measures light sensitivity at several loci (points) in the central retina. The test also captures retinal images. The five of eight patients responding to the high dose of AGTC-501 had improvements in retinal sensitivity of at least 7 decibels in 5 or more loci. Responses of the six patients receiving the low dose of the therapy were similar to untreated eyes in the high dose group.
AGTC-501 was well-tolerated and no clinically significant safety events were associated with treatment.
The XLRP gene therapy was delivered by a one-time subretinal injection. AGTC-501 uses a human-engineered adeno-associated virus (AAV), which works like a vast container system, to deliver healthy copies of the RPGR gene to cells in the retina.
Beacon plans to launch its Phase 2/3 VISTA clinical trial for AGTC-501 during the first half of 2024.
The Foundation Fighting Blindness funded successful canine studies of XLRP gene therapy at the University of Pennsylvania School of Veterinary Medicine that helped make the XLRP gene therapy clinical trial possible.
XLRP affects approximately 20,000 people in the US and EU. As an X-linked condition, XLRP usually affects males. Though females are usually unaffected carriers of XLRP, they sometimes have vision loss, as well. The condition causes constriction of vision, reduced vision in dark settings, and central vision loss, especially in later stages. Most males with XLRP are legally blind by the age of 45.
]]>Ascidian Therapeutics has received authorization from the US Food & Drug Administration to launch a Phase ½ clinical trial for ACDN-01, the company’s RNA editing therapy for people with Stargardt disease, an inherited form of macular degeneration caused by mutations in the ABCA4 gene. The company plans to begin enrollment for the clinical trial, known as STELLAR, during the first half of 2024.
Unlike genetic therapies that deliver an entire healthy gene (DNA) to replace the mutated gene, or which edit DNA, ACDN-01 re-writes RNA, the genetic message derived from DNA that cells read to make proteins. Healthy proteins are essential to the survival and function of all cells in the body, including those of the retina. ACDN-01 specifically re-writes RNA exons, the regions where mutations are most likely to occur for the ABCA4 gene. Ascidian estimates that ACDN-01 can address mutations in ABCA4 for a significant percentage of people with Stargardt disease because the editing replaces a large number of exons, all at once.
By targeting Stargardt disease at the RNA level, ACDN-01 overcomes two limitations with therapeutic approaches that replace or edit DNA. First, it circumvents the challenge of delivering the large ABCA4 gene which exceeds the capacity of the viral delivery systems known as adeno-associated viruses (AAVs) that are typically used in retinal gene therapies. Also, RNA editing avoids permanent, off-target DNA editing which is a potential risk with gene editing.
ACDN-01 is delivered by a one-time, subretinal injection.
The emerging treatment is the first RNA exon editor to enter clinical development for any disease and the only clinical-stage therapeutic targeting the genetic cause of Stargardt disease.
ACDN-01 has demonstrated efficient and durable RNA exon editing in a large animal model and in human retinal explants.
The Foundation and Ascidian collaborate closely. The Foundation provided data from its ProgSTAR natural history study on how Stargardt disease progresses for affected patients.
Stargardt disease affects approximately 30,000 people in the US. It is characterized by the accumulation of toxic byproducts from vitamin A metabolism in the retina, ultimately leading to retinal cell death and central vision loss. People with Stargardt disease can lose the ability to read, drive, and recognize faces. The condition is usually diagnosed in children or young adults, but age of onset, severity, and rate of progression can vary.
]]>Laboratoires Théa, the leading European developer of eye care products, has acquired two emerging antisense oligonucleotide (AON) treatments for inherited retinal diseases from ProQR Therapeutics. Both AON therapies — sepofarsen (LCA10) and ultevursen (USH2A) — previously demonstrated vision improvements in ProQR’s clinical trials.
In October 2023, Théa had announced termination of its agreement to acquire ProQR’s LCA10 and USH2A assets, but the companies have since moved forward to ultimately complete the acquisition.
Under the terms of the agreement, ProQR has received an initial payment of €8M and may be eligible for up to €165M in further development, regulatory, and commercial earn-out payments upon related achieved milestones, as well as double-digit royalties based on commercial sales in the US and EU.
The RD Fund, the venture philanthropy arm of the Foundation Fighting Blindness, invested in the development of ultevursen and supported ProQR’s effort to find a buyer for both of its ophthalmic assets.
“We are delighted that Théa’s acquisition of sepofarsen and ultevursen has been completed and to see these promising treatments move forward in clinical development,” says Jason Menzo, chief executive officer, Foundation Fighting Blindness. “Both emerging therapies have demonstrated encouraging results in human studies and provide hope for preserving and restoring vision for patients.”
Sepofarsen was developed for people with Leber congenital amaurosis 10 (LCA10) caused by the IVS26 mutation in the gene CEP290. Some patients in ProQR’s Phase 2/3 Illuminate clinical trial for sepofarsen had meaningful vision improvements. However, the treatment did not meet its primary trial endpoint, best-corrected visual acuity (BCVA), nor did it meet its secondary endpoint, navigation of a mobility course.
Ultevursen was developed for people with mutations in exon 13 of the USH2A gene which leads to Usher syndrome 2A or non-syndromic retinitis pigmentosa. In ProQR’s Phase 1/2 Stellar clinical trial, ultevursen demonstrated benefits in BCVA, static perimetry (retinal sensitivity), and retinal structure as measured by optical coherence tomography (OCT).
Both sepofarsen and ultevursen are comprised of tiny pieces of genetic material that are injected into the vitreous, the soft gel in the middle of the eye. The genetic material masks the disease mutation in RNA, the genetic messages that cells read to make proteins which are critical for the cells’ health and function. Masking the mutation enables cells to make the correct protein.
AONs can be advantageous when large retinal disease genes — such as CEP290 and USH2A — exceed the capacity of viral gene replacement delivery systems thereby making gene therapy development for these genes more challenging.
]]>KIO-301 was initially tested in people who have lost all or most of their photoreceptors, the retinal cells that make vision possible, to an advanced retinal disease. Known as a photoswitch, the molecule enables retinal ganglion cells to respond to light, thereby working like a back-up system for lost photoreceptors. Retinal ganglion cells, which are downstream from photoreceptors, often survive in advanced retinal disease but don’t naturally respond to light. KIO-301 is delivered by a standard injection into the vitreous, the soft gel in the middle of the eye. One administration of the therapy appears to be effective for about a month.
The six patients in ABACUS-1 were split into two groups of three. Cohort 1 patients had no light perception or bare light perception. Cohort 2 patients had enough vision to see hand motion or count fingers. Three doses of KIO-301 were evaluated.
Cohort 1 patients appeared to have improvements in their ability to perceive the direction of movement and/or location of a window or lighted exit.
Cohort 2 patients had improvements in visual fields (peripheral vision) as measured by a Goldmann perimeter. Cohort 2 patients receiving the high dose had improvements in visual acuity, as measured by a Berkeley Rudimentary Vision Test, a test designed to evaluate vision in people without enough vision to read any letters on a typical eye chart.
Functional MRI showed an increase in visual cortex activity for patients in the trial.
Eric Daniels, MD, Kiora’s chief development officer, noted that it is important not to come to any major conclusions about the drug at this early juncture, though the evaluation results “point in the right direction.”
“This drug appears to be safe and it may support re-animation of the retina,” said Dr. Daniels. “It merits further study, in this case, a controlled randomized study to further tease out the signal over randomness.”
Kiora is planning the Phase 2 Abacus-2 study at three sites in Australia. Twenty patients will be enrolled. Patients will receive monthly injections for three months. The study will be: controlled, double-masked (patients and treating doctors won’t know if they are getting treatment or control), and randomized (patients will be randomly assigned to control or treatment group). Control patients will go on to receive active drug in an open-label extension.
Kiora is planning to share trial data with the US Food & Drug Administration. The company hopes to expand the study to the US and EU.
The company is exploring the enrollment of patients with choroideremia and Stargardt disease in a future clinical trial.
The Foundation Fighting Blindness provided $1.3 million in funding through its Translational Research Acceleration Program and a Gund Harrington Scholar Award to Richard Kramer, PhD, University of California, Berkeley, for the development of related photoswitches for restoring vision.
]]>A Mass Eye and Ear research team led by Eric Pierce, MD, PhD, director of the Ocular Genomics Institute, and Jason Comander, MD, PhD, director of the Inherited Retinal Disorders Service, has determined that a high-dose vitamin A supplementation regimen does not slow vision loss in people with retinitis pigmentosa (RP). The new findings are from an analysis of additional data from the original 600-plus patient clinical trial at Mass Eye and Ear conducted by the late Eliot Berson, MD, between 1984 and 1991. Dr. Berson was the original director of the Berman-Gund Lab, the first research lab focused on inherited retinal diseases (IRDs) and the first lab funded by the Foundation.
Dr. Berson had reported that vitamin A supplementation modestly slowed loss of vision in people with RP. He also found that vitamin E supplementation accelerated vision loss. In the original vitamin A clinical trial, Dr. Berson measured patients’ vision over time, using the electroretinogram (ERG), a test which measures the retina’s electrical response to light.
While Dr. Pierce and his team found no overall benefit from vitamin A in the new analysis, their findings re-affirmed that people with RP should avoid vitamin E supplementation, because of its negative effect on retinal health. They noted that the AREDS2 supplement, which reduces the risk of advanced age-related macular degeneration (AMD) for those with intermediate-stage AMD, contains vitamin E and should therefore not be taken by RP patients. Regardless of the name or product label of a supplement, people with RP should check ingredients to ensure it doesn’t have vitamin E.
In the follow-up study, Dr. Pierce’s team re-analyzed the original patient data from Dr. Berson’s study along with additional patient data that was collected from the same patients after Dr. Berson’s analysis had ended. The team analyzed data from a total of 765 patients. The team identified the genetic cause of disease in 587 of those patients using blood samples collected from past clinical trials. However, there were not enough patients to definitively identify subsets of patients with specific genetic profiles who responded to vitamin A therapy.
Dr. Comander presented results from the new Mass Eye and Ear vitamin A and E study at the RD2023 meeting on retinal degenerative disease research held October 23-27, 2023, in Torremolinos, Spain. Results from the study were also published in June 2023 in the journal JCI Insight.
The Foundation Fighting Blindness provided funding for both the original and follow-up studies on vitamins A and E and was a sponsor of the RD2023 meeting. Dr. Comander acknowledged the Foundation for its decades-long support of RP research infrastructure at research centers like Mass Eye and Ear. “I am so grateful for this long-term support of the Foundation, without which we would not have been able to produce this invaluable knowledge of how different genetic forms of RP progress over the long term,” he said.
Dr. Comander noted that, at the time, Dr. Berson’s vitamin A clinical trial was groundbreaking because it was the first-ever study for people with RP and remains the largest ever for these patients. However, the results were always controversial in the IRD clinical research community, because vision improvements were minimal and ERGs are not the optimal tool for measuring vision changes over time.
“I feel that the lasting legacy of this study, regardless of the effect of the vitamins, is the detailed description of progression rates of different genetic types of RP,” said Dr. Comander. “It also confirmed how the genetic cause and electroretinogram results can help predict the course of disease, which may be quite helpful for future therapeutic clinical trials which measure progression rates.”
Researchers believe that vitamin A supplements might be harmful for people with Stargardt disease and related cone-rod dystrophies, but patients can eat a normal diet.
Patients should always consult with their physicians about changing any treatment or supplementation regimen. Dr. Comander said that RP patients who have been on vitamin A supplements for many years and feel they are doing well can continue the regimen under continued supervision of their doctor. Yearly liver function tests for patients taking the vitamin A supplementation regimen should be conducted.
]]>The biotech company Ocugen provided an update on the Phase ½ clinical trial for OCU400, its emerging, modifier gene therapy, which delivers copies of the NR2E3 gene to improve regulation of multiple functions in the retina including: photoreceptor maintenance and development, metabolism, phototransduction, inflammation, and cell survival. The company says OCU400 is designed to work for people with inherited retinal diseases caused by a broad range of gene mutations.
The latest report from the trial is for 12 patients who had follow-ups ranging from 6 to 12 months after subretinal injection of OCU400 in one eye. OCU400 had a favorable safety profile in the Phase ½ clinical trial. Also, 8 of 12 patients had stabilization or improvement in all three of the following visual function measures: best corrected visual acuity (BCVA), low luminance visual acuity (LLVA), and navigation of a multi-luminance mobility test (MLMT).
The trial enrolled people with: retinitis pigmentosa (RP) caused by autosomal dominant mutations in rhodopsin (RHO); RP caused by autosomal dominant mutations in NR2E3; and RP, enhanced S-cone syndrome; and Goldmann-Favre syndrome caused by autosomal recessive mutations in NR2E3. The trial is currently enrolling pediatric patients with RHO and NR2E3 mutations as well as adult and pediatric patients with Leber congenital amaurosis (LCA) caused by CEP290 mutations.
Ocugen has also started recruiting for two Phase ½ clinical trials for its modifier gene therapies for people with geographic atrophy (GA) associated with advanced dry age-related macular degeneration and Stargardt disease. The company plans to start dosing patients in the trials by the end of 2023.
These emerging therapies — OCU410 for GA and OCU410ST for Stargardt disease — are designed to deliver copies of the RORA gene to retinal cells to improve lipid metabolism and reduce inflammation. Ocugen believes boosting RORA expression will slow retinal degeneration and vision loss in people with GA and Stargardt disease.
OCU400, OCU410, and OCU410ST use human-engineered adeno-associated viruses (AAVs) to deliver the therapeutic genes to retinal cells. The gene therapies are administered using a one-time, subretinal injection.
]]>Opus Genetics, a company developing gene therapies for people with inherited retinal diseases, has dosed the first patient in its Phase ½ gene therapy clinical for Leber congenital amaurosis 5 (LCA5), which causes significant vision loss in children. The Phase ½ clinical trial, enrolling nine adult patients, is being conducted at the University of Pennsylvania. Once safety in adults has been established and confirmed by the US Food and Drug Administration, Opus plans to dose pediatric patients.
Known as OPGx-001, the gene therapy uses a human-engineered adeno-associated virus (AAV) to deliver healthy copies of the LCA5 gene to the retinas of patients, augmenting the mutated copies causing vision loss. The therapy is administered through a one-time injection underneath the retina. Researchers believe gene therapies will be effective for many years, perhaps the life of the patient.
The LCA5 gene-therapy clinical trial is the first launched by Opus, a company originally conceived and formed by the Foundation Fighting Blindness. Founded in 2021, Opus received $19 million in seed funding from the Foundation’s RD Fund, a venture philanthropy fund for emerging retinal disease therapies in or nearing early-stage clinical trials. The company is led by Ben Yerxa, PhD, former chief executive officer of the Foundation.
]]>Examples of FY2023 grants include:
“Excitingly, 15 of the new awardees for FY23 are researchers never previously funded by the Foundation,” said Claire Gelfman, PhD, chief scientific officer at the Foundation. “We make the greatest impact in driving our urgent mission to eradicate all retinal degenerative diseases when we continually infuse our efforts with new ideas and research talent.”
Research grants were selected after a rigorous review process conducted by the Foundation’s Scientific Advisory Board, which is comprised of more than 60 of the world’s leading retinal scientists and clinicians.
The Foundation’s current research portfolio funds a total of 93 grants. The research projects are conducted by more than 96 research investigators at 71 institutions around the world. In addition to funding researchers in the United States, the Foundation funding extends internationally to laboratories in Australia, Belgium, Brazil, Canada, Denmark, England, Finland, France, Germany, Israel, Italy, Mexico, the Netherlands, Poland, Spain, and Switzerland.
“Correcting previously untreatable retinal degenerative diseases using twin prime editing.”
Dr. Palczewski is developing a novel gene-editing technology called twin prime editing for treating a model of Stargardt disease. He is also developing a twin prime editing framework to address other inherited retinal degenerative diseases. Prime editing enables changes (corrections) to DNA to be made through single-strand breaks which are safer and more reliable than double-strand breaks used in earlier gene-editing technologies. Twin prime editing introduces additional flexibility by enabling the deletion and/or insertion of large DNA sequences for addressing a broader range of mutations.
“Clinical translation of a mutation-independent treatment for hereditary retinal degeneration using BlockPKG, an inhibitory cGMP analogue.”
Mireca Medicines is developing a drug and delivery system targeting excessive cGMP-signaling that leads to loss of photoreceptors. This signaling molecule can over-activate the enzyme protein kinase G (PKG). This group previously discovered that inhibition of this enzyme can bring the rapid degeneration of light-sensitive cells to a halt and thereby preserving retinal structure and function. The group is working to advance the emerging treatment toward a clinical trial.
“Evaluating mitigation strategies for intravitreal viral vector-mediated inflammation across animal models.”
Dr. Pepple is investigating novel strategies for mitigating ocular inflammation which can result from intravitreal injection of viral gene therapies. She is evaluating animal model data and performing detailed immunologic characterization of the non-human primate eyes during ocular inflammation to provide clinical-pathologic correlations and biomarker validation for use in human clinical studies. A robust and evidence-based approach to preventing ocular inflammation following intravitreal adeno-associated virus (AAV)-mediated gene therapy is a critical unmet need.
“Targeting the molecule FUS for neuroprotection: A novel therapeutic approach in retinal degeneration.”
Dr. Rohrer and her team are determining if a small molecule (MC16) can extend the lifespan of retinal cells by targeting mitochondria, which produce cellular energy. The molecule has the potential to significantly decrease the age-dependent and/or stress-dependent movement of a protein associated with mitochondrial dysfunction observed in retinal degeneration.
“Lipid nanoparticle-mediated gene editing for IRD patients harboring PRPH2 mutations.”
Dr. Ryals is investigating prime editing delivered by lipid nanoparticles for correcting mutations in the PRPH2 gene, which is correlated with certain retinal diseases. Dr. Ryals is deriving induced pluripotent stem cells (iPSCs) from patient blood and differentiating them into human retinal organoids for therapeutic testing. Retinal organoids are three-dimensional structures, which have some similarities to the human retina (including the photoreceptors), thereby serving as effective models of retinal development and testing platforms.
“ARMS2/HTRA1 in non–cell-autonomous oxidative and anti-inflammatory therapeutic targeting.”
Drs. Tsang and Olah are using CRISPR/Cas9 gene-editing to identify genetic variations and mutations that lead to age-related macular degeneration (AMD). They are also investigating stress signals from microglia (resident immune cells of the brain and retina) in AMD that might be a therapeutic target to reduce AMD-related cell death. They will also explore whether the presence of at least one low-risk ARMS2/HTRA1 allele (gene copy) maintains oxidative, anti-inflammatory, and overall cellular health in microglia.
“A novel, rationally designed pharmacological approach to countering vision loss in a preclinical model of MERTK-associated retinitis pigmentosa.”
Dr. Finnemann and her team are determining if an early-onset inflammatory response in retinal pigment epithelial (RPE) cells precedes photoreceptor degeneration. RPE cells provide provide critical support for photoreceptors. If successful in uncovering this novel disease pathway, a therapeutic strategy testing anti-inflammatory drugs for MERTK-associated retinitis pigmentosa will be proposed to prevent or significantly delay retinal degeneration.
“In vivo retinal RNA editing using the cellular adenosine deaminase acting on RNA (ADAR) enzyme.”
Dr. Sharon and his team are developing an RNA editing technology to correct specific retinal disease-causing mutations. They are delivering novel biological machinery to the retina that uses enzymes called “adenosine deaminase acting on RNA” or ADAR that serves as molecular editors to correct a specific mutation in RNA. The technique is like gene editing but instead of editing the gene, this technique edits RNA, which is the transcript or message read from the gene to produce protein.
“Deciphering the impact of ABCA4 genetic variants of unknown significance in inherited retinal disease prognosis.”
Dr. Biswas-Fiss is using computational modeling and experiments to determine whether ABCA4 variants of unknown significance (VUSs) lead to ABCA4-related disease. Resolving these VUSs is critical for patients to meet inclusion criteria in clinical trials for ABCA4 therapies. Mutations in ABCA4 cause the vast majority of Stargardt disease cases.
“Restoring extracellular matrix signaling between Müller glia and photoreceptors for therapies of inherited retinal degeneration.”
Dr. Chen is seeking to better understand the role of muller glia (MG) in the early stages of inherited retinal diseases. MG provide functional and structural support to photoreceptors and other cells in the retina. Using human-derived mini-retinas, she is determining the cause of MG dysfunction, assessing the negative impact of MG cell dysfunction on photoreceptor development, and exploring the feasibility of rescuing photoreceptors by restoring extracellular matrix signaling, which typically helps cells attach and communicate with nearby cells.
“Long non-coding RNAs (lncRNAs) as molecular drivers and therapeutics targets of inherited retinal disease.”
Dr. Coppieters is using in-house and public data sets to identify inherited retinal disease (IRD)-related long non-coding RNA (lncRNA) in the retina and retinal pigment epithelium to create a comprehensive catalog of lncRNA with a potential role in IRDs. Long non-coding RNA does not convert code into protein but are part of regulating gene expression at the right time and place. This project will evaluate the therapeutic potential of selected lncRNAs in IRD patient models.
“Identification, validation and modulation of uncharacterized splicing mutations in inherited retinal diseases.”
Dr. Irimia is seeking to uncover novel genetic variants that cause splicing misregulation, leading to inherited retinal diseases (IRDs). This project aims to identify new variants in IRD genes that change the way the different pieces of a gene are combined together to make a functional protein. Potential variants identified through genetic sequencing will be tested in the lab to see if their presence has a detrimental effect on gene production and retinal cell biology.
“Knock-down and replacement therapy for dominant CRX-associated retinopathies.”
Dr. Petersen-Jones is testing a gene knock-down strategy for dominant CRX-associated inherited retinal diseases (including CRX-associated autosomal dominant Leber congenital amaurosis). A single, mutated copy of CRX can cause disease. This strategy will stop the bad copy of CRX and add back a good copy of CRX using artificial microRNA. MicroRNA are small non-coding RNA involved in RNA silencing and regulating gene expression. Dr. Petersen-Jones will test this knockdown and replace technique on CRX as a proof of concept that can be modified for other dominantly inherited diseases.
“Prime editing for PRPH2 inherited retinal dystrophies.”
Dr. Quinn is testing a prime editing technique for multiple mutations in PRPH2 using patient-derived retinal organoids. Prime editing is a gene editing technique that splices directly at the site of the mutations and switches out a bad copy of the gene with a good copy. Successful completion of this project will establish a preclinical pathway for proof-of-concept for PRPH2 prime editing therapeutics and lay the foundation for the same strategy to be applied to other IRDs.
“Reprogramming human MG to retinal progenitors and neurons.”
Dr. Reh is exploring approaches for enabling retinal cells called Müller glia (MG) to sprout new photoreceptors. Previous experiments have shown this is possible by delivering a transcription factor known as ascl1 to the MG. Dr. Reh is now optimizing photoreceptor regeneration in a 3D culture system that more closely resembles the human retina. He is seeking to improve and optimize the viral delivery of a gene expressing ascl1 for moving the approach closer to evaluation in a clinical trial.
“Targeting microglia to prevent retinal neuron loss in inherited retinal degenerations.”
Dr. Samuel is attempting to limit the damage done by microglia (clean-up cells) in the retina by removing signal regulatory protein alpha (SIRPα). Removing SIRPα should slow excessive cleaning activity in the cell-based model and may improve survival of transplanted photoreceptors. This project could potentially lead to a therapeutic approach for slowing vision loss for a broad range of inherited retinal diseases.
“Inner retinal dysfunction in retinitis pigmentosa.”
Dr. Hyde is using a novel electroretinography (ERG) protocol in animal models of retinal degeneration to determine whether retinal remodeling leads to aberrant responses from inner retinal neurons that mask relevant responses to visual stimuli. ERG is a non-invasive means to measure the electrical responses of various retinal cell types to light. Inner retinal remodeling can cause aberrant inner retinal responses that limit the potential for functional improvement from therapies that improve photoreceptor function.
“Deciphering the missing heritability in inherited retinal diseases with targeted long-read genome sequencing.”
Dr. Mustafi is using long-read DNA sequencing technology to identify heritability in cases where standard genetic testing does not provide an answer due to hidden non-coding variants. Long-read sequencing is used to identify large structural variants including large DNA deletions and insertions. Autosomal recessive inheritance requires two mutated variants, and in many cases, only one or no variants are located in patients with clinical features of an inherited retinal disease (IRD). Dr. Mustafi will analyze cases where only one variant for ABCA4 and USH2A patients have been identified through genetic testing and more in-depth mapping of the genome may result in the detection of a second non-coding variant. This data will be used to expand the gene panel testing of IRD patients to look for rare variants currently not included in standard testing.
“Investigating the heterogeneity of photoreceptor precursor cells for retinal regeneration.”
Dr. Uyhazi is seeking to better understand the different stages of photoreceptor precursor cells during development in order to identify the optimal cell type for cell-based therapies, including transplantation. Each novel subpopulation of photoreceptor precursor cells will be tested for their integration into the retina, and if they can increase photoreceptor cell generation.
“Spectral properties of ERG oscillatory potentials in hereditary retinal dystrophies prior to and following the application of gene therapy employing a novel gel-based AAV vector delivery system.”
Dr. Ayalon will study the spectral properties of ERG oscillatory potentials (OPs) in hereditary retinal dystrophies and will evaluate if the frequency domain of OPs can be used as a new diagnostic tool. The OPs may be an earlier, and more sensitive, indicator of an inherited retinal disease. Dr. Ayalon will also investigate if the gel-based epiretinal adeno-associated virus (AAV) delivery system has a better retinal cell transduction efficiency than subretinal and intravitreal injections.
“Exploring retinal structure and function in patients with CDH23-associated Usher syndrome.”
Dr. Guimaraes will study patients previously confirmed, via genetic testing, with Usher syndrome type 1D due to CDH23 mutations. His aim is to perform several tests, using state-of-the-art cutting-edge technology, to analyze the structure and function of the retina in a group of 25 patients within a period of 12 months. This will be the first study to systematically assess detailed photoreceptor structure and correlate it with measures of visual sensitivity in Usher type 1D.
“Ultracompact hand-held swept-source optical coherence tomography as a novel diagnostic modality for early-onset retinal dystrophies.”
Dr. Maldonado is investigating the use of hand-held optical coherence tomography (OCT) to image young pediatric patients, with and without early-onset retinal disease, to establish an ideal protocol for the use of the hand-held system in standard clinical care and clinical trials. The team will also obtain biomarker data related to retinal degeneration, data related to the effect of specific genetic variants, and insights into foveal development using hand-held OCT.
“Creation of a translational nonhuman primate model of Usher syndrome 1B.”
Dr. Neuringer and her team will expand a gene-edited nonhuman primate (NHP) model of Usher syndrome for initial tests of gene therapy. The expanded animal models of Usher syndrome 1B (USH1B) will enable studies to determine how closely primates harboring USH1B genetic variation resemble the human disease. The model will also be used to test a new type of gene therapy that uses a dual adeno-associated virus (AAV) platform that can facilitate the delivery of the MYO7A gene, which is too large to fit in a single AAV vector.
“Characterization of a large animal Stargardt disease model – suitability for translational therapy trials.”
Dr. Petersen-Jones will establish a breeding colony of dogs with Stargardt disease (ABCA4-affected) and determine if the disease progression can be accelerated with vitamin A supplementation. The retina of Stargardt disease patients accumulates material called bisretinoid, a toxic byproduct of vitamin A metabolism, that fluoresces with UV light. As part of the study, Dr. Petersen-Jones will standardize a way of measuring the amount of autofluorescence in affected dogs. This has the potential to be a new standard monitoring measurement to grade the rate of disease progression.
“2023 Cold Spring Harbor Lab – Vision: A Platform for Linking Circuits, Behavior & Perception.”
Vision: A Platform for Linking Circuits, Behavior & Perception was held in Long Island, New York, between June 16-July 1, 2023. The purpose of the course was to bring together students and faculty for in-depth and high level discussions of modern approaches for probing how specific cell types and circuits give rise to defined categories of visual perception and behavior. It was also designed to address novel strategies aimed at overcoming diseases that compromise visual function.
]]>SparingVision, a French company developing therapies for ocular conditions including inherited retinal diseases, has dosed the first cohort of patients at the low dose in its Phase ½ clinical trial for its gene-independent, cone-preserving therapy known as SPVN06 for retinitis pigmentosa (RP). The company received a positive recommendation from the Data Safety Monitoring Board (DSMB) to dose the second cohort at the medium dose. Known as PRODYGY, the trial is being conducted at the University of Pittsburgh Medical Center and Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO XV-XX), Paris.
SparingVision plans to enroll a total of 33 RP patients who have disease-causing mutations in PDE6A, PDE6B, or RHO. Initially, the trial is enrolling patients with visual acuity between 20/200 and 20/400 and a visual field of 20 degrees or less. Patients with better vision will be enrolled later in the Phase ½ trial.
The Foundation’s RD Fund, a venture philanthropy fund for emerging therapies that are in or nearing early-stage clinical trials, is one of the funders for SparingVision. The Foundation also provided several years of research grant funding for the preclinical development of SPVN06.
SPVN06 expresses a protein called rod-derived cone-viability factor (RdCVF), a protein naturally occurring in the retina identified by SparingVision co-founders José Sahel, MD, and Thierry Léveillard, PhD, at the Institut de la Vision. The scientists demonstrated in laboratory studies that RdCVF prevented or slowed the degeneration of cones, the cells in the retina that provide central and color vision and enable people to read, drive, and recognize faces. RdCVF is naturally secreted by rods, the retinal cells that provide night and peripheral vision. In people with RP, the progressive loss of rods leads to loss of cones.
SPVN06 is administrated through a one-time subretinal injection. The therapy uses a human-engineered adeno-associated virus (AAV), which works like a vast container system, to deliver DNA which expresses RdCVF in retinal cells.
RP affects more than two million people worldwide. The retinal disease is usually diagnosed in childhood, progressively leading to legal or total blindness in adulthood.
Further details can be found on Clinicaltrials.gov (https://clinicaltrials.gov/study/NCT05748873) or by contacting the genetic counselors at University of Pittsburgh Medical Center at: retinal.dystrophy@upmc.edu.
]]>Atsena Therapeutics, a company developing gene therapies for inherited retinal diseases (IRDs), has dosed the first person in a Phase ½ clinical trial for its X-linked retinoschisis (XLRS) gene therapy, ATSN-201. Known as the Lighthouse Study, the clinical trial is evaluating ATSN-201 in male patients ages 6-64 with a clinical diagnosis of XLRS caused by pathogenic or likely pathogenic mutations in the gene RS1. The 18-participant clinical trial is taking place at the Children’s Hospital of Los Angeles and the Oregon Health & Science University.
Atsena’s emerging XLRS gene therapy is injected subretinally (underneath the retina). The company says this approach gets the treatment more effectively to the area of the retina where the treatment is needed – i.e., the cavities in the central retina caused by the splitting of retinal layers. The gene therapy uses a specially designed adeno-associated viral delivery system (AAV.SPR) that is able to reach the fragile fovea, the tiny pit in the central retina responsible for visual acuity, without an injection in the foveal region. The AAV.SPR was designed in the lab of Shannon Boye, PhD, a retinal gene therapy pioneer from the University of Florida and co-founder of Atsena.
“Dosing the first patient in the LIGHTHOUSE study marks a significant milestone for Atsena and the XLRS community,” said Kenji Fujita, MD, chief medical officer at Atsena Therapeutics, in a press release. “We are excited to be utilizing AAV.SPR in the clinic, as it has the potential to revolutionize the treatment of XLRS, as well as other inherited retinal disorders. Spreading laterally beyond the subretinal injection site, AAV.SPR facilitates the safe delivery of RS1 to photoreceptors in the central retina/fovea.”
The RD Fund, the Foundation’s venture philanthropy fund for advancing emerging treatments into and through early stage clinical trials, is a founding investor in Atsena.
XLRS is caused by mutations in the gene RS1 which expresses a protein called retinoschisin — a protein that plays a critical role in the maintenance of the retinal structure and cell-to-cell adhesion. As an X-linked condition, XLRS usually affects males with females as unaffected carriers. XLRS is usually diagnosed in boys before the age of 10. Approximately 30,000 people in the US and EU are affected by XLRS.
Atsena has also reported vision improvements for patients in a Phase ½ gene therapy clinical trial for Leber congenital amaurosis 1 (LCA1) which is caused by GUCY2D mutations. The company also has a dual-vector gene therapy in preclinical development for Usher syndrome 1B, which is caused by MYO7A mutations.
]]>Regeneron says treatment frequency for 8 mg doses of Eylea are as follows:
FDA approval for the new dosing regimen was based on results from two clinical trials that enrolled more than 1,600 patients combined. In the two trials, the new, higher dosing regimen with less frequent injection was similar in safety and efficacy to the previous dosing regimen of 2 mgs every 2 months (after 3 initial monthly doses).
Vision loss from wet AMD, DME, and DR are all caused by the growth of leaky blood vessels that lead to retinal cell and vision loss. Eylea works by blocking a protein called vascular endothelial growth factor (VEGF) which causes growth of leaky blood vessels.
Injections of Eylea are made into the vitreous, the soft gel-like substance in the middle of the eye. Injections are typically performed in an eye doctor’s office. Patients receive local anesthetic to minimize discomfort.
]]>Astellas expects IZERVAY to be available in the US two to four weeks from the date of FDA approval. The treatment is administered through intravitreal injections — injections made in the soft gel in the middle of the eye — in a doctor’s office.
Astellas says that approximately 1.5 million people in the US have GA.
“We are excited to have a new treatment for geographic atrophy which is a leading cause of devastating central vision loss for people 55 and older,” says Jason Menzo, chief executive officer, Foundation Fighting Blindness. “IZERVAY has the opportunity to help people maintain their independence and quality of life by preserving their ability to read, drive, and see faces of loved ones.”
IZERVAY met the primary endpoint, slowing the growth rate of GA lesions, in two global Phase 3 clinical trials. In the 448-participant GATHER1 clinical trial, IZERVAY slowed lesion growth by 27.7 percent at 12 months of treatment. In the 286-participant GATHER2 clinical trial, IZERVAY slowed lesion growth by 14.3 percent at 12 months of treatment. In both trials, patients were randomized to receive either 2 mgs of IZERVAY or a sham monthly.
IZERVAY is designed to work by inhibiting the C5 protein, which is part of the complement system. Researchers believe that the overactive complement system, part of the innate immune system, is a key culprit in the development of AMD. While the complement system plays an important role in fighting off viruses, bacteria, and other pathogens, it can be damaging when overactive.
More than 10 million people in the US and 150 million worldwide have AMD. Vision loss from GA is caused by the accumulation of toxic deposits underneath the retina called drusen. The condition can cause loss of retinal pigment epithelial (RPE) cells which provide essential support for photoreceptors, the retinal cells that process light to make vision possible. The degeneration of RPE cells ultimately leads to loss of photoreceptors and central vision loss. In AMD, the macula, the central region of the retina, is affected most.
]]>Tinlarebant is an emerging oral medication designed to slow vision loss by reducing the growth rate of lesions — i.e., areas of retinal cell loss — associated with GA, a leading cause of blindness in people 55 and older, and Stargardt disease, the leading form of inherited, early-onset macular degeneration.
Belite also has its DRAGON Phase 3 clinical trial for Tinlarebant underway for adolescent patients with Stargardt disease.
In many macular conditions, retinal cell loss is caused by the accumulation of toxic byproducts associated with vitamin A metabolism. Tinlarebant was developed to reduce formation of these toxins.
Vitamin A is a nutrient that is essential for vision — it binds with proteins known as opsins to enable photoreceptors (rods and cones) to respond to light. However, damaging toxic byproducts from vitamin A processing accumulate in people with many macular diseases. The macula, the central region of the retina, enables people to read, drive, and see faces. Macular degenerations cause loss of central vision and visual acuity.
]]>PYC Therapeutics, an Australia-based developer of RNA therapies, has launched a Phase 1 clinical trial for its RNA therapy known as VP-001 for people with retinitis pigmentosa 11 (RP11) which is caused by mutations in the gene PRPF31. The 20-person clinical trial is taking place in the US. The first patient was dosed at the Retina Foundation of the Southwest in Dallas. Three doses of VP-001 are being evaluated. VP-001 is administered through an intravitreal injection. Investigators will be evaluating safety as well as a number of measures of retinal structure and visual function.
“We are delighted to initiate a clinical trial of the first therapy specifically for RP11 patients,” says Sri Mudumba, Ph.D., chief research and development officer at PYC. “We believe our innovative RNA therapy and delivery technologies are ideal for targeting inherited retinal diseases. These conditions are a critical unmet need.”
PYC has reported that approximately 1 in 100,000 people have RP11. That equates to nearly 80,000 people affected worldwide.
PYC’s emerging therapies are designed to modify RNA, the genetic messages that cells read to make the proteins which are critical to the health and function of all the cells in the body. By modifying RNA, protein expression can be boosted or reduced, depending on the therapeutic need.
In people with RP11, one copy of their PRPF31 gene is normal and producing a relatively normal level of protein while the other PRPF31 copy is mutated and not producing sufficient protein. The overall reduced level of PRPF31 protein for RP11 patients leads to retinal degeneration and vision loss.
Researchers from PYC found that by downregulating the activity of a different gene, CNOT3, they could boost PRPF31 protein expression. So, they developed VP-001, a tiny piece of synthetic genetic material designed to alter the RNA expressed by the gene CNOT3, thereby increasing PRPF31 protein expression.
]]>A multi-disciplinary retinal research team from the University of Wisconsin-Madison (UWM) has been awarded a five-year, $29 million U19 grant from the National Institutes of Health (NIH) Common Fund to develop CRISPR/Cas9 gene-editing treatments for two inherited retinal conditions: Best disease caused by the R218C mutation in the BEST1 gene and Leber congenital amaurosis 16 (LCA16) caused by the W53X mutation in the KCNJ13 gene. Known as The CRISPR Vision Program: Nonviral Genome Editing Platforms to Treat Inherited Retinal Channelopathies, the grant will advance the LCA16 and Best disease treatments toward evaluation in clinical trials.
“We are delighted to receive significant support through the Common Fund grant to drive the development of innovative gene-editing treatments for these blinding retinal diseases,” says Bikash Pattnaik, PhD, associate professor of pediatrics, ophthalmology and visual sciences at UWM, and one of the project’s lead investigators. “We also appreciate earlier support from the Foundation Fighting Blindness for Best disease and LCA16 research that positioned us well to receive the award.”
The other lead UWM investigators for the project include Krishanu Saha, PhD, associate professor of biomedical engineering and faculty member of the Wisconsin Institute for Discovery (WID); David Gamm, MD, PhD, professor of ophthalmology and visual sciences and director of the McPherson Eye Research Institution; and Shaoqin “Sarah” Gong, PhD, professor of ophthalmology and visual sciences and biomedical engineering and WID faculty. Investigators at Spotlight Therapeutics, the Morgridge Institute for Research, and the UMass Chan Medical School will work closely with the UWM team on the project.
The NIH Common Fund is a unique resource for support of high-risk, innovative endeavors with the potential for extraordinary impact. Common Fund programs are short-term, goal-driven strategic investments, with deliverables intended to catalyze research across multiple biomedical research disciplines. The LCA16 and Best disease research award is administered by the National Institute of Neurological Disorders and Stroke (NINDS) on behalf of the NIH.
The Foundation has accepted an invitation to be a member of the External Advisory Board for the award. Chad Jackson, PhD, the Foundation’s senior director of preclinical translational Research, will advise on project design, analysis, interpretation, and regulatory strategy.
Best disease is a form of inherited macular degeneration that can lead to significant central vision loss. LCA16 causes significant central and peripheral vision loss in young children. The gene mutations for both conditions affect the function and health of retinal pigment epithelial (RPE) cells which provide critical support for photoreceptors, the retinal cells that process light to make vision possible. Loss and dysfunction of RPE cells lead to loss of photoreceptors.
CRISPR/Cas9 gene editing is an emerging therapeutic approach that works like a pair of molecular scissors to cut out or modify the mutated region of the gene. Gene editing is different from gene (replacement) therapy. In gene therapy, copies of an entirely new gene are delivered to the retina to replace the defective copies. In CRISPR/Cas9 gene editing, only the mutated region of the gene is corrected.
For both the LCA16 and Best disease projects, the investigators will use induced pluripotent stem cells (iPSCs) to create human models of the conditions to evaluate the CRISPR/Cas9 treatments. The team will extract a small sample of skin or blood cells from patients and tweak the cells so they revert to a stem-cell-like state. Then, the cells will be coaxed forward to differentiate into RPE cells. The team will also evaluate the LCA16 CRISPR/Cas9 treatment in a mouse model.
The investigators will evaluate two non-viral delivery approaches for emerging treatments. One approach will use nanoparticles — tiny manmade particles with a diameter smaller than that of human hair — to deliver the CRISPR/Cas9 treatment into the RPE cells. The other delivery approach will use ribonucleoproteins (RNPs) for treatment delivery. RNPs can be modified with a cell-targeting antibody and a cell-penetrating peptide to facilitate delivery of the CRISPR/Cas9 treatment into cells and enable efficient editing of the targeted DNA. Both the nanoparticle and the RNP delivery systems can potentially lower the risk of inflammation and off-target editing. These attributes may provide opportunities for safe redosing of the therapy, potentially overcoming a key limitation of traditional viral gene therapies.
]]>Beacon will also complete data collection for the achromatopsia clinical trials (CNGA3, CNGB3) previously sponsored by AGTC, though it will not continue the development of either achromatopsia product candidates.
Beacon will be led by David Fellows, the former chief executive officer of Nightstar Therapeutics. Nadia Waheed, MD, formerly of Gyroscope Therapeutics, will be Beacon’s chief medical officer. Abraham Scaria, PhD, formerly of AGTC, will serve as Beacon’s chief scientific officer.
Dr. MacLaren is a co-founder of Beacon and will serve as a scientific advisor.
]]>
Coave Therapeutics, a French biotechnology company, announced that its gene therapy for people with retinitis pigmentosa (RP) caused by mutations in the gene PDE6B improved visual function at 12 months after dosing for a subgroup of six patients with less-advanced disease in a 17-patient, Phase ½ clinical trial.
The company said the results support preparation for a registrational trial for the PDE6B gene therapy. With success in a registrational or pivotal trial, the company would likely seek marketing approval from regulators such as the European Medicines Agency and/or the US Food & Drug Administration.
Coave has received approval from regulators to dose six additional patients, ages 13 to 25 years of age with less-advanced disease, in the current Phase ½ clinical trial.
Improvements for the trial subgroup were reported in: best-corrected visual acuity (BCVA); visual fields; microperimetry which measures sensitivity in the central retina; full-field sensitivity (FST), which measures general retinal sensitivity; and the ability to navigate a mobility course.
Two dose levels of the gene therapy were evaluated in the Phase ½ clinical trial. Only the patient’s worse-seeing eye was treated. Those patients with improved visual function received the higher dose.
Known as CTx-PDE6B, the gene therapy is administered by an injection underneath the retina. The gene therapy uses a human-engineered adeno-associated virus (AAV) to deliver copies of healthy PDE6B genes to the photoreceptors in the retina to augment the mutated gene copies.
]]>The theme for this year’s Innovation Summit was “Defining the Preclinical to Clinical Roadmap,” with several presentations emphasizing design of clinical trials for emerging therapies. Many talks included reviews of natural history studies and endpoint for preclinical and clinical trials. Presenters shared both success stories and lessons learned from their studies with the goal of informing design of future human studies and boosting the potential for their success.
“The Innovation Summit is an essential meeting for therapy developers, because there’s no other forum or venue where they can glean so much data and knowledge from the translational and clinical trial front lines,” said Claire Gelfman, PhD, chief scientific officer at the Foundation. “The overarching goal of the Summit is to help move the field forward.”
Summit co-hosts were Casey’s Paul Yang, MD, PhD, and Renee Ryals, PhD, and the Foundation’s Amy Laster, PhD.
Summit sponsors:
Session Summaries
Session 1: Clinical Trial Design
Establishing Genome Interpretation Criteria to Improve Treatment Eligibility and Access to Treatments and Clinical Trials
Rob Hufnagel, MD, PhD, National Eye Institute, National Institutes of Health
The Clinical Genome Resource (ClinGen) is a National Institutes of Health (NIH)-funded international consortium dedicated to standardizing the interpretation of genetic variants for use in precision medicine and research. Gene curation and cataloguing improves the value of genetic testing as a diagnostic tool and resource for identifying patients eligible for clinical trials and the growing pipeline of genetic therapies.
Dr. Hufnagel is co-chair of the ClinGen Ocular Clinical Domain Working Group (CDWG) and co-chairs the 26-member Retina Gene Curation Expert Panel (GCEP). Thus far, the Retina GCEP has curated 41 inherited retinal disease (IRD) genes and published them on the ClinGen website. Their goal is to curate a total of 250 IRD genes.
REDI Working Group Initiative #1: Clinical Trial Endpoints from the RUSH2A Natural History Study
Jacque Duncan, MD, University of California, San Francisco
The Regulatory Endpoints and Trial Design for IRDs (REDI) was established by the Foundation Fighting Blindness in collaboration with researchers and industry to develop new clinical trial endpoints for emerging IRD therapies that can be validated by the FDA. The ultimate goal is to boost the chances that future therapies will move through trials successfully and gain FDA approval.
Dr. Duncan said that results from the four-year, Foundation-funded, RUSH2A natural history study for people with USH2A mutations will be used to identify a new endpoint that can be validated by the FDA. All 105 RUSH2A patients (eight years of age or older), with either Usher syndrome 2A or non-syndromic retinitis pigmentosa (RP) caused by USH2A mutations, have completed their four years of annual visits. The preliminary conclusion is that full-field sensitivity (FST) may be the best measure for detecting vision changes. EZ area, best-corrected visual acuity (BCVA), and static perimetry (including Hill of Vision) were also evaluated.
The Pro-EYS Natural History Study: Background and Baseline
Rachel Huckfeldt, MD, PhD, Mass Eye and Ear, Harvard Medical School
The Foundation launched the four-year Pro-EYS natural history study to better understand rate of progression, structure-function relationships, and risk factors for people with RP caused by mutations in the EYS gene, which are a common cause of autosomal recessive RP globally. The study will also help identify potential endpoints for future clinical trials of emerging therapies.
Pro-EYS concluded enrollment with 103 patients (18 years of age or older) in 2021. Four-year follow-ups should be completed in 2025. Functional assessments include: best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), contrast sensitivity, full-field static perimetry, microperimetry, full-field stimulus test (FST), and full-field electroretinograms (ERGs). Structural assessments include: spectral domain optical coherence tomography (OCT) and short-wavelength and long-wavelength autofluorescence. The researchers are also obtaining patient reported outcomes.
Functional Outcome Measures for Clinical Trials of Stargardt Disease: Insights from a Prospective Natural History Study
Brett Jeffrey, PhD, National Eye Institute, National Institutes of Health
Dr. Jeffrey reviewed results from a Stargardt disease natural history that was conducted by the National Eye Institute (NEI) from 2012 through 2018 with Brian Brooks, MD, PhD, and Maximillian Pfau, MD, as lead investigators. The study was launched to identify optimal endpoints for the NEI’s metformin clinical trial for Stargardt disease which launched in late 2020.
The natural history study enrolled 67 patients (12 years of age or older) who were followed for five years. Functional measures for the study included: BCVA, low vision Cambridge Color Test, fundus-guided perimetry, and ERG. Structural measures included: color fundus photography, OCT, and fundus autofluorescence (FAF). Median age at baseline was 37 years. Median BCVA was 20/125.
Ultimately, the primary outcome measure chosen for the metformin clinical trial was rate of square root growth of EZ band loss (as captured by OCT). Secondary outcomes measures included the rate of photopic and scotopic sensitivity loss (as captured by MP3), rate of square root growth of definitely decreased autofluorescence (DDAF), and change in BCVA.
Patient-Reported Outcome Measures for Natural History Studies and Clinical Trials in Inherited Retinal Diseases
Thiran Jayasundera, MD, Kellogg Eye Center, University of Michigan
Dr. Jayasundera reported on two IRD patient questionnaires that may have utility as endpoints.
The Michigan Retinal Degeneration Questionnaire (MRDQ) is a psychometrically validated patient-reported outcomes measure that evaluates seven unidimensional domains: central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral vision, mesopic peripheral vision, and photosensitivity. Results from the MRDQ produce a reliable score for a person’s visual ability that does not show significant test-retest variability across repeated administration.
The Michigan Vision-Related Anxiety Questionnaire (MVAQ) can be used to determine quantitatively whether a person’s rod or cone dysfunction is the cause of their anxiety.
Yearly Change in Rod-Mediated Visual Function in the RUSH2A Natural History Story
David Birch, PhD, Retina Foundation of the Southwest
Dr. Birch presented on two tests that were used in RUSH2A to measure rod function: FST and dark-adapted visual field (DAVF). Given results from the study, he believes both may be useful and reliable endpoints for measuring rod function in human trials.
FST measures the lowest luminance that a flash of light can be detected by the patient’s retina. It provides a general measurement of rod and/or cone function. FST does not provide information on retinal structure. However, it can be a good test for advanced vision loss, especially for people who cannot fixate, which may be necessary for other vision tests.
Dark-Adapted Visual Fields (DAVFs) measure visual thresholds throughout the visual field and show whether they are rod or cone mediated.
In the RUSH2A study, FST of general rod and cone function correlated with changes in retinal structure as measured by EZ Area. DAVF showed rate of vision loss progression that was comparable to progression measured by FST.
Evolutionary Design of Tests of Functional Vision for Inherited Retinal Degenerations
Jean Bennett, MD, PhD, University of Pennsylvania
The development of the multi-luminance mobility test (MLMT) for evaluation of patients in the LUXTURNA® clinical trial was groundbreaking, because other FDA-validated endpoints were not effective for measuring vision changes in people with IRDs, especially children with advanced vision loss from conditions such as Leber congenital amaurosis (LCA).
However, the MLMT has drawbacks. Among its limitations, the MLMT requires a large space, it is time-consuming to set-up and re-configure, the course involves tripping hazards for the patient, and there is difficulty in ensuring uniform illumination. Also, a reading center is required to tabulate testing results.
Dr. Bennett and her colleagues are developing virtual reality (VR) mobility testing that offers many advantages over the MLMT. With VR testing, several objects encountered in daily living can be presented (e.g., cabinet with an open door, wet floor sign, skateboard, tables, etc.). VR testing requires little space. Luminance levels are more consistent. And, it can present 35 different configurations so the course layouts cannot be easily memorized. Also, testing variables can be altered relevant to the patient’s disease.
A pre-validation study has been completed and the FDA has granted the team an Investigational Device Exemption for patients eight years of age and older.
The University of Pennsylvania plans to launch a company to commercialize the VR system.
The Streetlab Low Vision Center to Assess the Performance of Patients with Visual Deficit in Daily Life
José Sahel, MD, Institut de la Vision, University of Pittsburgh Medical Center
Dr. Sahel and his team created an indoor platform for simulating an urban environment for objectively evaluating the functional vision of patients with IRDs and other low-vision conditions. Known as Streetlab, the platform has adjustable scenery, a 3D sound system, and light and color controls. The Motion Capture System captures behavioral measures including the user’s gait, head direction, gaze direction, and movement patterns.
The team also developed the Mobility Standardized Test in Virtual Reality (MOSTVR) to simulate natural walking in a maze. The system provides multiple standardized routes and lighting conditions. Performance measures include: walking speed, errors (e.g., collisions), head and feet movements, and eye-tracking. The VR system was enjoyable for 73 percent of participants and 78 percent of participants with RP felt the VR test accurately represented their navigational difficulties in daily life.
Design and Development of Novel Endpoints for Clinical Trials of Multi-Characteristic Opsin Enabled Vision Restoration in Patients with Advanced RP and Stargardt Disease
Nell (Ninel) Gregori, MD, Bascom Palmer Eye Institute, University of Miami
Dr. Gregori reviewed Nanscope’s emerging optogenetic therapy, MCO-010, which is being developed as a potential treatment for advanced RP, Stargardt disease, and age-related macular degeneration (AMD). The gene therapy, injected intravitreally and delivered to bipolar cells, expresses a multi-characteristic opsin (MCO) which is designed to respond to ambient light and refresh quickly to avoid blurred vision.
Dr. Gregori reported on results from a Phase 1/2a clinical trial in India of MCO-010 for 11 patients with advanced RP. She said that most patients had improvements in visual acuity (as measured by the Freiburg test) of 0.3 logMAR or better. Most enrollees also had improved ability to navigate simple Y- and A-mobility tests and identify three different shapes when undergoing a 3D multi-luminance shape discrimination test (MLSDT).
Dr. Gregori also mentioned the Phase 2b clinical trials of MCO-010 are underway for patients with advanced RP and Stargardt disease. Results for the Phase 2b trial were covered in a later presentation by Nanoscope’s Aaron Osborne.
Session 2: Optogenetics
Worldwide Multicenter Ocular Imaging Study (EyeConic) to Identify Patients for Cone-Based Optogenetic Therapy
Hendrik Scholl, MD, Institute of Molecular and Clinical Ophthalmology Basel (IOB)
Dr. Scholl and his IOB colleagues are developing a cone-based optogenetic therapy for patients with advanced RP (and related diseases) that is delivered to dormant cones (nonfunctional cones with shortened or absent outer segments). Post-mortem studies revealed that people with advanced RP retain cone cell bodies with very short or absent outer segments. Dr. Scholl and his team believe cone-targeted optogenetics will provide better restored vision than optogenetic approaches targeting ganglion or bipolar cells.
The team conducted the international EyeConic Eye Study to evaluate dormant cone populations in people with advanced vision loss due to an IRD. The study enrolled 291 patients (446 eyes) across 11 centers. They concluded that a substantial number of patients with low vision would be excellent candidates for a clinical trial of IOB’s cone-targeted optogenetic therapy. They also observed that disease duration is not predictive of foveal volume, though longer disease duration is associated with lower visual function. They also concluded that there is no strong correlation between genotype and foveal volume.
A Brighter Future: Restoring Vision with the Power of Optogenetics
Peter Francis, MD, PhD, Ray Therapeutics
Ray Therapeutics is developing an optogenetic therapy that they believe can restore meaningful levels of visual acuity, visual field, contrast sensitivity, and motion detection without the need for glasses or goggles to enhance the light coming into the eye. The company is conducting IND-enabling studies to gain authorization to launch a clinical trial for people with advanced RP. Ray also has preclinical development programs for Stargardt disease and geographic atrophy (advanced dry AMD).
The company is delivering its treatment through an intravitreal injection to ganglion cells for expression of its proprietary ChRown protein that responds to a broad range of light wavelengths and refreshes quickly to avoid blurring during motion detection. Known as RTx-015, the therapy restored visual acuity and contrast sensitivity to blind mice.
Ray is in partnership with Forge Biologics for therapy manufacturing.
Session 3: Preclinical Gene Therapies
A Novel, Non-Viral Approach to Delivering Full-Length ABCA4 to Photoreceptors
Gayathri Ramaswamy, PhD, Intergalactic Therapeutics
Intergalactic is developing non-viral delivery of ABCA4 using its C3DNA technology, which has been engineered using synthetic biology tools to assemble modular elements into a closed loop. The covalently closed, circular (C3) construction enables C3DNA to be taken up by cells and expressed, without insertion into the host genome.
The company’s COMET system — Cellular delivery of genetic Material by Electro-Transfer — uses a pulsed electric field to delivery large genetic cargo (ABCA4-C3DNA) without immunogenic issues.
Intergalactic’s ABCA4 therapy provided 12 months of protein expression in a preclinical model. They plan to file an IND in the first half of 2024.
Development of Endpoints for Clinical Translation of BEST1 Adeno-Associated Virus (AAV) Gene Therapy
Ash Jayagopal, MD, Opus Genetics
Dr. Jayagopal reported that Opus is planning to launch a gene therapy trial in 2024 for people with retinal diseases caused by BEST1 mutations.
In Best vitelliform macular dystrophy (BVMD), an autosomal dominant disease, visual acuity loss is relatively slow. The eruption of the vitelliform lesion, usually later in disease, leads to significant central vision loss. In contrast, autosomal recessive BEST1 (ARB) disease rarely leads to the vitelliform lesion, but the disease onset is early and progression of vision loss is more aggressive. Canine BEST1 models have pathologic features similar to both BVMD and ARB and have provided a platform for compelling proof-of-concept for a BEST1 gene therapy. BEST1 gene therapy is likely better for loss-of-function mutations (not gain-of-function).
Based on results from human natural history studies, Opus believes OCT with functional measures (e.g., dark-adapted chromatic perimetry) may be used to identify anatomical targets for gene therapy delivery. Microperimetry may be a good approval endpoint in clinical trials.
Exon Editing in Stargardt Disease and Other ABCA4 Retinopathies
Jay Barth, MD, Ascidian Therapeutics
Ascidian is developing an RNA exon-editing therapy for Stargardt disease and other retinal conditions caused by ABCA4 mutations. The emerging therapy, delivered by an AAV, leverages cells’ endogenous exon-splicing machinery. The therapy replaces exons 1-22 in ABCA4; approximately 75 percent of people with disease caused by ABCA4 mutations have a mutation in exon 1-22.
The company has demonstrated proof-of-concept for the approach in non-human primates. They demonstrated that more than 30 percent of ABCA4 protein carried the corrected exons 1-22 six months after treatment.
IND-enabling studies are underway, and manufacturing is online.
Gene Therapy for PDE6C Achromatopsia: Progress and Challenges
Ala Moshiri, MD, PhD, UC Davis Eye Center
Dr. Moshiri and his team evaluated a PDE6C gene therapy in a non-human primate (NHP) model of achromatopsia. Mutations in the gene can also cause cone-rod dystrophy.
The high dose of the therapy delivered using an AAV5 vector, rescued cone (green, red, blue) function in the first NHP cohort and was durable out to 20 months. Rescue in a second cohort was delayed. Dr. Moshiri said that no pre-injection steroids were given to the second cohort and that inflammation may account for delay in efficacy. He also said that the optimal age for intervention may be younger than those animals in the second cohort.
PRODYGY: Study Design of a First-in-Human Trial of SPVN06 Gene-Independent Gene Therapy in Patients with Rod-Cone Dystrophy
Isabelle Audo, MD, PhD, Centre Hospitalier National d’Ophthalmologie (CHNO) des Quinze-Vingts Sarbonne Université
Dr. Audo reviewed the clinical study design for SPVN06, a gene-agnostic gene therapy for preserving cone function. In patients with RP and other rod-cone dystrophies, cones degenerate because of the loss of rods. SPVN06 expresses rod-derived cone viability factors (RdCVF and RDCVFL), which are normally expressed by rods. RdCVF boosts glycolysis (sugar metabolism) in cones. RDCVFL is a strong anti-oxidant.
The 33-participant, dose-escalation, Phase ½ trial has received authorization from the FDA to launch in the US at the University of Pittsburgh Medical Center. The European Medicines Agency (EMA) has authorized a clinical trial launch in Paris at the CHNO. The first injection is expected in mid-May. The trial is enrolling RP patients with mutations in PDE6A, PDE6B, and RHO.
Nanoscope Therapeutics: Pioneering a New Wave of Optogenetic Therapeutics for Vision Restoration
Aaron Osborne, MD, Nanoscope
Dr. Osborne reviewed results from Nanoscope’s Phase 2b clinical trial for its optogenetic therapy for people with advanced RP. Known as MCO-010, the emerging treatment uses an AAV to deliver copies of a gene to bipolar cells to express a multi-characteristic opsin, which is activated by a broad spectrum of light, including ambient light. No goggles or glasses are needed with this optogenetic approach.
The study enrolled 27 patients with vision of 1.9 LogMAR or worse in the study eye. 18 patients received MCO-011; 9 received a sham injection. Dr. Osborne said 12 of 18 MCO-010 patients were able to navigate a simple multi-luminance Y-mobility test (MLYMT) with light reduced by two or more levels (vs. 3 out of 9 patients in the sham group). Also, 10 of 18 patients were able to correctly identify shapes when performing a multi-luminance shape discrimination test (MLSDT) with light reduced by two or more levels (vs. 2 out of 9 patients in sham group). BCVA (as measured by the Freiburg acuity test) improved by 0.3 LogMAR or more in 7 of 18 patients (vs. 1 out of 9 patients in the sham group).
Keynote Address: Blazing the Trail for Trials after the LUXTURNA Honeymoon:
Optimization of Endpoints and Managing Expectations in Gene Therapy Trials for IRDs and Lessons Learned from a Phase 3 Trial (Illuminate)
Bart Leroy, MD, PhD, Ghent University Hospital, Children’s Hospital of Philadelphia
Dr. Leroy said LUXTURNA® development was like hacking a path through the jungle with a machete. The development process leading to FDA approval was difficult because no one had previously navigated this path for an ocular gene therapy. But the therapy performed well in the clinical trial and was FDA-approved in 2017. Dr. Leroy noted one of his patients continues to do well 15 years after being dosed in the trial.
Some people who have received LUXTURNA have experienced chorioretinal atrophy. Dr. Leroy said the atrophy occurred at three locations in the retina: at the site of injection, within the treatment area, and/or beyond the treatment area. Some cases require further investigation. Dr. Leroy emphasized the need for tight control of inflammation.
Dr. Leroy also reviewed the clinical trials for sepofarsen, an antisense oligonucleotide (AON) developed by ProQR for targeting the frequent IVS26 mutation in CEP290 which leads to LCA10. Despite early severe vision loss, LCA10 patients retain retinal structure (i.e., surviving photoreceptors). Sepofarsen corrects RNA splicing to address the mutation’s effect.
Delivered through an intravitreal injection, sepofarsen improved overall cone and rod sensitivity as measured by FST in an 11-patient Phase 1/2b clinical trial. The treatment then moved into a 36-participant Phase 2/3 clinical trial at 14 sites in nine countries. Some treated patients (14/23) had improved BCVA, but some patients receiving the sham (3/12) also had improved BCVA. However, more treated patients had self-reported improvements (using the VFQ-25 questionnaire) than those receiving sham.
Based on guidance from the regulatory authorities, the Phase 2/3 study compared the treated eyes of patients to the untreated eyes of sham patients. Using this comparison, sepofarsen did not meet the primary endpoint (change in BCVA) in the trial. However, when comparing the patient’s treated eye to their own untreated eye, sepofarsen did show meaningful improvement. Dr. Leroy noted that day-to-day natural variability in patients’ vision and the small number of patients enrolled in the trial also presented challenges for meeting the primary endpoint.
The EMA recommended that ProQR launch a second Phase 2/3 trial. But given the lack of additional LCA10 patients and the cost of another trial, ProQR decided to conserve capital to advance its Axiomer RNA-editing program and seek a partner for its retinal AON programs (LCA10, USH2A, and RP-RHO). The company continues to provide compassionate access to sepofarsen and ultevursen (USH2A).
In conclusion, Dr. Leroy said that AONs are a promising technology, especially for mutation hotspots in genes too big for AAVs, and should be explored further. (He noted that all of his sepofarsen patients reported vision improvement.) Also, the IRD therapy development community needs to educate regulators about IRDs so that better endpoints can be developed and clinical trial designs improved. Multistakeholder meetings, including the Foundation’s REDI Working Group, are being organized to discuss how researchers, regulators, and families can move forward together.
Session 4: Clinical Gene Therapy
Efficacy and Safety Endpoints in Patients with ABCA4-Associated Stargardt Disease Participating in Gene Therapy Clinical Trials
Maria Parker, MD, Casey Eye Institute, Oregon Health and Science University
Dr. Parker reviewed three-year results for the Phase 1/2a clinical trial for StarGen, a lentiviral-based, ABCA4 gene therapy developed by Oxford Biomedica. The dose-escalation study enrolled 22 patients. Subretinal treatment with StarGen was well-tolerated with only one case of ocular hypertension.
Functional endpoints included: BCVA, static perimetry, kinetic perimetry, full-field ERG, and multifocal ERG. Structural endpoints included: color fundus photography, FAF, and spectral domain OCT. Hill of Vision, a measure developed by OHSU’s Richard Weleber, MD, provided 3D surface models of vision and defects, enabling quantitative functional measures in static perimetry.
No clinically significant changes in visual function were found to be attributable to the treatment. The utility of perimetry and electrophysiology was likely limited in patients with poor vision due to high variability or poor signal detection. Multimodal imaging did not reveal evidence of clinically meaningful efficacy, but was effective for assessing safety in Stargardt disease.
Gene Therapy for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR — Results of the Phase 2/3 Clinical Trial
Robert MacLaren, MD. PhD, University of Oxford
Dr. MacLaren discussed a gene therapy for RPGR and presented data from the Phase 2/3 clinical trial. Dr. MacLaren noted that the ORF15 isoform of RPGR, which is the photoreceptor-specific isoform, is difficult to clone because of multiple GA (the nucleotides Guanine and Adenine) repeats. The repeats create cloning errors, which make it difficult to create stable gene therapy vectors. Spontaneous mutations continue to arise in the general population due to ORF15 instability.
Dr. MacLaren also showed that RPGRORF15 glutamylation is critical for function: impaired glutamylation leads to cone-dominated phenotypes with truncating distal ORF15 variants. Despite these challenges, a suitable gene therapy vector was generated through codon optimization.
The Biogen Phase 2/3 clinical trial for RPGR gene therapy was designed for 45 patients, but only 29 were recruited due to COVID. The trial had three cohorts: low dose, high dose, and control. The Phase 3 clinical trial didn’t meet its primary endpoint of greater than 7 db improvement in at least 5 points due to improvement in both dosed and control patients. Patients also showed improvement in LLVA. Dr. MacLaren attributed the trial’s failure to the small number of enrolled patients.
He ended his talk by saying that he would be reporting more about the RPGR gene therapy at a later date and had positive announcements of next steps in due course.
Full-Field Scotopic Threshold Improvement Following Voretigene Neparvovec (LUXTURNA) Treatment Correlates with Chorioretinal Atrophy
Aaron Nagiel, MD, PhD, Children’s Hospital of Los Angeles (CHLA), USC Roski Eye Center
The CHLA treated 70 eyes of 35 patients with LUXTURNA — patients ranged in age from 20 months to 44 years.
Subretinal deposits and perifoveal chorioretinal atrophy have been widely reported by LUXTURNA treatment centers. Dr. Nagiel said possible explanations include ocular factors, vector-related toxicity, and surgical delivery.
In a collaborative retrospective study with CHLA and the University of Tübingen, it was determined that eyes that developed atrophy had better baseline BCVA. Also, they observed that eyes with more FST improvement were at higher risk of atrophy. Dr. Nagiel added that the patients at most risk for atrophy were school age to young adults.
Dr. Nagiel noted that patients didn’t notice the atrophy because the fovea was spared.
RGX-314 Subretinal Delivery Program: Gene Therapy for Neovascular AMD
Sherry Van Everen, PhD, REGENXBIO
REGENXBIO currently has two Phase 3 clinical trials underway for subretinal delivery of its wet AMD gene therapy, RGX-314. The company also has a Phase 2 clinical trial underway for suprachoroidal delivery of RGX-314 for wet AMD.
Dr. Van Everen shared results from the long-term follow-up (up to five years) of 37 patients who were dosed in the Phase ½ clinical trial for subretinal delivery of RGX-314 for wet AMD. With a single injection of RGX-314, patients in medium and high-dose cohorts demonstrated a long-term, durable treatment effect of stable or improved visual acuity and meaningful reductions in anti-VEGF rescue injections.
Based on a Phase 2 pharmacodynamic study, the company’s commercial-ready, bioreactor (BRX) manufacturing process is expected to support future commercialization of RGX-314.
Ixoberogene Soroparvovec (Ixo-vec) Intravitreal Gene Therapy for Neovascular Age-Related Macular Degeneration: End of Study Results from the 2-Year OPTIC Trial and Lessons Learned
Kali Stasi, MD, PhD, Adverum Biotechnologies
Ixo-vec is a gene therapy for wet AMD that expresses aflibercept. Adverum enrolled 30 patients in its OPTIC 2-year safety study for Ixo-vec. The therapy was generally well-tolerated. The most common adverse event was mild-moderate, dose-dependent inflammation which was responsive to topical steroids. Therapeutic levels of Ixo-vec were sustained through three years with both dose levels. A 98 percent reduction in rescue anti-VEGF injections was reported for participants receiving the high dose. An 80 percent reduction in rescue injections was observed for those getting the low dose. BCVA was maintained and central subfield thickness was reduced with both doses.
Adverum is further developing Ixo-vec in its LUNA Phase 2 clinical trial to determine optimal dosing and the optimal prophylactic regimen for inflammation.
Six-Month Safety and Efficacy of ATSN-101 in Patients with Biallelic Mutations in GUCY2D Causing LCA1
Christine Kay, MD, Vitreo Retinal Associates of Gainesville
Dr. Kay said that, despite significant vision loss, people with GUCY2D mutations (LCA1) retain retinal structure over their lifetime, making them potential candidates for gene augmentation therapy.
Developed by Atsena Therapeutics, ATSN-101 is an AAV5-based subretinal gene therapy that delivers a normal copy of the GUCY2D gene. The Phase ½ clinical trial enrolled 15 patients. BCVA, FST, MLMT, and the VFQ-25 questionnaire are secondary endpoints.
No drug-related serious adverse events were reported. Infrequent ocular inflammation was minimal and treatable.
Four of six subjects demonstrated either a maximum MLMT score of 6, or a 2 or more light level improvement. The FDA considers a 2-level improvement to be clinically meaningful. Two high-dose patients demonstrated greater than 0.3 logMAR improvement in BCVA. No treated eyes had a decrease in BCVA. Significant improvement in dark-adapted FST was seen for cones, rods, and cones and rods combined.
Session 5: Preclinical and Clinical Cell-Based Therapy
Hypoimmune Retinal Pigment Epithelial Cells Evade Immune Response Following Transplantation into the Non-Human Primate without Immune Suppression
Trevor McGill, PhD, Sana Biotechnology, Inc.
Dr. McGill reported that immune suppression is very much needed but also challenging in the transplantation of allogenic cells (cells that come from a donor other than the patient). The various forms of immune suppression have many undesirable side effects.
Sana is developing therapeutic cells, derived from induced pluripotent stem cells (iPSC), that have been genetically engineered to block reactions by the adaptive and innate immune systems. Their hypoimmune (HIP) cell lines should be transplantable into any human recipient without the need for immunosuppression.
Dr. McGill reported that HIP retinal pigment epithelial (RPE) cells evaded the innate and adaptive immune response when transplanted in the subretinal space of NHPs without evidence of an immune rejection.
A Multimodal Neuroprotective Stem Cell Tissue Engineering Solution for Treating Retinitis Pigmentosa
Pierre Dromel, PhD, InGel Therapeutics
InGel is developing neuroprotective ocular cell therapies that are delivered into the eye using hydrogel scaffolds which mimic the human vitreous. Dr. Dromel said the benefits of the hydrogel include the improvement of cell viability after injection and immune system evasion. Because the hydrogel adheres to the inner limiting membrane, unwanted diffusion is avoided with intravitreal injections. The hydrogel has been safe in multiple animal models.
The company is planning to deliver the rod-based therapy to protect photoreceptor cells for people with RP and dry AMD. They hope to launch a clinical trial for the treatment, known as IGT001, in 2025. IGT001 performed well in rd1 mice, which have RP caused by PDE6B mutations, and in an RP (RHO knockout) model.
Phase ½ Open-Label Study of Implantation of hESC-Derived RPE in Patients with RP: First Safety Results
Christelle Monville, PhD, i-Stem
Dr. Monville presented early results from i-Stem’s 12-patient clinical trial at XV-XX Hospital in Paris for a 14.5 mm2 RPE cell patch for people with RP (LRAT, MERTK mutations). The patch is comprised of RPE derived from human embryonic stem cells (hESCs) placed on a human amniotic membrane. Patients received immunosuppression (mycophenolate mofetil) for one year. The goal is to preserve vision in early disease.
Dr. Monville reported that safety was good overall. Two patients had sectoral thinning of the inner retinal layer. For one patient, the patch slid. She said 75 percent of patients had stable visual acuity at one year. Twenty-five percent had decreased acuity. Three patients had improved fixation.
Phase 1/2a Study of OpRegen®, Human Allogenic RPE Cells, in Patients with Geographic Atrophy
Eyal Banin, MD, PhD, Hadassah-Hebrew University Medical Center
A total of 24 patients (12 legally blind in cohorts 1-3, 12 less impaired vision in cohort 4) with geographic atrophy (GA) received RPE cells in the Phase 1/2a trial. Immunosuppression was applied with tacrolimus and mycophenolate. Most adverse events were mild. Epiretinal membrane developed in 16 patients (clinically significant in 3).
Patients in cohort 4 had an average of a 7.6 letter gain in BCVA. Three patients in cohort 4 (25 percent) had a BCVA gain of 15 letters or more.
Dr. Banin said that there was preliminary evidence of outer retinal structure improvement, particularly in cohort 4 patients. The improvements are maintained in some patients for up to year four years with follow-up continuing.
A Phase 2a study evaluating the success of OpRegen delivery to target GA areas is enrolling.
A Phase 1/2a, Open-Label, Prospective Study of Subretinally Transplanted Human Retinal Progenitor Cells in Patients with RP
Jason Comander, MD, PhD, Mass Eye and Ear
A total of 29 participants with RP received ReNeuron’s human retinal progenitor cells (hRPC, mostly rods) in the clinical trial. Cell doses ranged from 0.25 million to 2.0 million cells. (The 1.0 and 2.0 million cell treatments were cryopreserved.) The worse-seeing eye was treated in each participant.
Three patients receiving the 1.0 million cell dose had initial BCVA improvement of 25 to 31 letters, but vision declined to near baseline by 24 months. Five of the seven patients receiving 2 million cells experienced a reduction in vision due to increased surgical complications with the higher dose. Surgical complications included development of epiretinal membranes and vitreoschisis.
Dr. Comander said the investigators did not know if the transplanted cells integrated into the host retina.
Intravitreal CD34+ Stem Cells from Bone Marrow for Retinitis Pigmentosa
Susanna Park, MD, PhD, University of California, Davis
Dr. Park discussed that CD34+ stem cells, derived from bone marrow, have natural repair effects. CD34+ cells are being used in allogenic bone marrow transplantation for leukemia, lymphoma, and inherited blood disorders. They are also in clinical trials for cardiomyopathy. In preclinical studies, human CD34+ cells homed into ischemic and degenerating retina.
Dr. Park and her team launched a six-patient Phase 1 clinical trial of autologous CD34+ from bone marrow for people with macular degeneration, RP, retinal vein occlusion, and diabetic retinopathy. Cells were delivered by an intravitreal injection. The treatment was well-tolerated and the approach deemed feasible. Four of six eyes gained two or more lines of vision on an ETDRS eye chart.
The team has an ongoing Phase 1 trial for seven RP patients and a Phase 1/2a trial for 16 people with central retinal vein occlusion.
jCyte Retinal Progenitor Cells for Treatment of RP
Henry Klassen, MD, PhD
Dr. Klassen said that jCyte’s jCells® (human retinal progenitor cells, hRPC) are a “living factory of retinal neurotrophic factors.” An emerging gene-agnostic therapy to preserve vison in people with RP, they are delivered intravitreally and can be re-injected.
In a Phase 2b clinical trial, 85 participants were divided into three cohorts — those receiving 6 million cells (n=27), those receiving 3 million cells (n=27), and those getting the sham (n=29). Overall, jCells® and the procedure were well-tolerated. Participants had baseline BCVA between 20/80 and 20/800 in the study eye.
At 12 months from baseline, 39 percent of patients receiving 6 million cells had BCVA improvement of 10 or more letters. In the 3 million cell cohort, 16 percent had BCVA improvement of 10 or more letters. In the sham group, 19 percent had BCVA improvement of 10 or more letters. Significant improvements for treated eyes were also seen in contrast sensitivity, kinetic visual fields, and mobility-related visual function (as captured by the VFQ-48 questionnaire).
Dr. Klassen noted that reliable BCVA measurements for RP require low baseline differences in BCVA for the patients’ two eyes. Also, mean BCVA change in subjects with greater than 8 degrees of a central visual field was more reliable.
Further clinical development of jCells® is planned.
]]>Atsena Therapeutics, a company developing gene therapies for inherited retinal diseases (IRDs), has received authorization from the US Food and Drug Administration (FDA) to launch a Phase ½ clinical trial for its X-linked retinoschisis (XLRS) gene therapy, ATSN-201. Known as The Lighthouse Study, the clinical trial will evaluate ATSN-201 in male patients ages 6-65 with a clinical diagnosis of XLRS caused by pathogenic or likely pathogenic mutations in the gene RS1. The company plans to initiate the trial in mid-2023.
Atsena’s emerging XLRS gene therapy is injected subretinally (underneath the retina). The company says this approach gets the treatment more effectively to the area of the retina where the treatment is needed – i.e., the cavities in the central retina caused by the splitting of retinal layers. The gene therapy uses a specially designed adeno-associated viral delivery system (AAV.SPR) that is able to reach the fragile fovea, the tiny pit in the central retina responsible for visual acuity, without an injection in the foveal region.
“The FDA’s clearance of the IND application for ATSN-201 marks a significant milestone for Atsena,” said Kenji Fujita, MD, chief medical officer of Atsena Therapeutics. “We’re excited to advance this investigational gene therapy that leverages our novel spreading capsid known as AAV.SPR into the clinic for people living with XLRS. XLRS is the leading cause of macular degeneration in young males and there are currently no approved treatments, so we have a compelling opportunity to address a significant unmet need.”
The RD Fund, the Foundation’s venture philanthropy fund for advancing emerging treatments into and through early stage clinical trials, is a founding investor in Atsena.
“We are delighted to see Atsena launch its second clinical trial for an IRD,” said Rusty Kelley, PhD, managing director of the Foundation’s RD Fund and an Atsena Board observer. “XLRS is a challenging retinal condition and a critical unmet need. We believe Atsena’s innovative, spreading-vector technology, developed by co-founder Shannon Boye’s group, provides an excellent opportunity to overcome delivery hurdles faced by other XLRS gene therapy developers that did not advance past early stage clinical trials.”
XLRS is caused by mutations in the gene RS1 which expresses a protein called retinoschisin — a protein that plays a critical role in the maintenance of the retinal structure and cell-to-cell adhesion. As an X-linked condition, XLRS usually affects males with females as unaffected carriers. XLRS is usually diagnosed in boys before the age of 10. Approximately 30,000 people in the US and EU are affected by XLRS.”
Atsena also recently reported vision improvements for patients in a Phase ½ gene therapy clinical trial for Leber congenital amaurosis 1 (LCA1) which is caused by GUCY2D mutations. The company also has a dual-vector gene therapy in preclinical development for Usher syndrome 1B, which is caused by MYO7A mutations.
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