Summary of the Eighth Annual Retinal Cell & Gene Therapy Innovation Summit 2023
Eye On the Cure Research News
The Retinal Cell and Gene Therapy Innovation Summit has emerged as one of the most essential events for researchers and companies developing treatments and cures for retinal degenerative diseases. In its eighth year, the Innovation Summit featured 30 presentations from retina experts from around the world with more than 300 people in attendance.
The Retinal Cell and Gene Therapy Innovation Summit has emerged as one of the most essential events for researchers and companies developing treatments and cures for retinal degenerative diseases. In its eighth year, the Innovation Summit featured 30 presentations from retina experts from around the world with more than 300 people in attendance. Hosted by the Foundation Fighting Blindness and the Casey Eye Institute at Oregon Health & Science University, the sold-out event was held on April 21, just prior to the 2023 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in New Orleans. While the ARVO meeting is the world's largest eye research conference, with nearly 10,000 attendees this year, the Innovation Summit provided an unparalleled focus on potential therapies, many of which are in clinical trials, for the entire spectrum of retinal degenerative diseases.
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.
- Gold: Apellis, Janssen, 4DMT, Astellas, Spark
- Silver: SparingVision, Adverum, MeiraGTx, Nanoscope, InFocus, Atsena, Glaukos, Regenexbio
- Patron: Nacuity, Lexitas
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 1/2 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 1/2 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 1/2 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 1/2 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.