Foundation Hosts Workshop on USH1B Research and Therapy Development
Emerging dual-vector gene therapies to address current cargo-size limitations were highlighted during the meeting.
The Foundation Fighting Blindness brought together more than 120 researchers, therapy developers, industry executives, and families for its virtual USH1B workshop on September 13, 2021, to discuss the opportunities and challenges in developing treatments for Usher syndrome type 1B (USH1B). Participants discussed in detail USH1B disease pathology, disease models, clinical characteristics, and therapeutic opportunities.
Usher syndrome type 1B is a particularly challenging condition on many fronts. While we have made progress in understanding the disease and investigating numerous therapeutic prospects, there’s clearly much more work that needs to be done.
The meeting was co-chaired by José-Alain Sahel, MD, University of Pittsburgh Medical Center and the Institut de la Vision in Paris, and Shannon Boye, PhD, University of Florida and Atsena Therapeutics.
"Usher syndrome type 1B is a particularly challenging condition on many fronts. While we have made progress in understanding the disease and investigating numerous therapeutic prospects, there's clearly much more work that needs to be done," said Dr. Sahel. "The workshop was an important step in determining the necessary actions to get us closer to validating effective therapies and engaging all the partners, especially the patients and their families."
Usher syndrome is a devastating diagnosis — it’s an inherited condition causing combined vision and hearing loss, and potentially problems with balance. The disease affects about 25,000 people in the US and 400,000 worldwide. USH1B is the most severe form of Usher syndrome causing profound hearing loss at birth and progressive vision loss and balance problems. Approximately 40 percent of people with Usher syndrome have USH1B.
"Imagine having to navigate the world blind, deaf, and without balance. USH1B is an assault on the primary senses. We’re not just fighting the early unmet and rapid progression of vision loss, we’re also battling congenital deafness and severe balance issues,” said Justin Porcano, a workshop participant whose three-year-old daughter has USH1B. “The workshop was a critical step in the right direction for understanding the gaps in research for this underserved disorder, but what we do next is what really matters."
Usher syndrome was the last thing that Justin and Rosalyn Porcano expected for their daughter, Lia, when she was born in March 2018. But Lia failed her hearing test when she was just 12 hours old. Two weeks later, they learned Lia was completely deaf. In August, results from genetic testing revealed that the Porcano’s daughter had USH1B and would progressively lose vision, as well. They were devastated and frightened. During the workshop, Justin said how “a lack of control to help my child” was so incredibly difficult for him and his wife. But the Porcanos quickly took action and founded Save Sight Now, a nonprofit to raise money for USH1B research funded by the Foundation Fighting Blindness. They raised $285,000 in their first year.
Twenty-four-year-old David Applegate from Portland, Oregon, expressed his urgent need for a treatment. “I've been plagued with the fear of losing my independence right at the time when I'm on the cusp of moving out. I want more than anything to be able to make my own way in life, to have a family and a path of my own, and it constantly feels like those dreams are hanging in the balance,” he said.
Maryrose Sylvester, a Foundation Board Vice Chair, and Steve Browne, a Foundation National Trustee, also spoke compellingly about their daughters’ challenges with USH1B and the urgent need for a treatment to address their progressive vision loss.
Todd Durham, PhD, senior VP of clinical outcomes research at the Foundation, reported survey results for USH1B patients and caregivers identified through the My Retina Tracker Patient Registry and other patient networks. Among the results: 42 of 78 respondents said that loss of vision and ultimately blindness was their biggest worry. Also, the top three motivations for participating in a clinical trial (58 respondents) were: 1) stopping vision loss progression, 2) improving lost vision, and 3) finding a cure.
The MYO7A gene
Claire Gelfman, PhD, the Foundation’s chief scientific officer, and Aziz El-Amraoui, PhD, Institut Pasteur, reviewed the roles of the protein expressed by the MYO7A gene, which when mutated, causes USH1B.
MYO7A plays an important role in the health and function of photoreceptors and retinal pigment epithelial cells in the retina, as well as in hair cells in the cochlea of the inner ear. In the retina, MYO7A is a protein expressed in both rod and cone photoreceptors, the cells that make vision possible, and retinal pigment epithelial cells which support the photoreceptors.
Researchers have determined that MYO7A helps other proteins, molecules, and organelles move through cells, so that cells remain healthy and function properly. MYO7A also helps retinal cells maintain their shape. Serge Picaud, PhD, Institut de la Vision, said he believes that MYO7A also enables photoreceptors to orient properly.
Animal models: Retinal researchers frequently use rodent models for evaluating therapies. The USH1B mice with mutations in the MYO7A gene experience hearing defects (not unlike those seen in people with USH1B), but interestingly, don’t have vision loss. Researchers believe this is because the rodents lack calyceal processes, which act like a girdle in the middle of the photoreceptor, where the sensory part of the cell (outer segment) connects with the cell body (inner segment).
Hannah Nonarath, Medical College of Wisconsin, presented her work in USH1B zebrafish and David Gamm, MD, PhD, University of Wisconsin-Madison, discussed his development of human USH1B retinal organoids derived from induced pluripotent stem cells. While both models are helpful in understanding USH1B, they have limitations in their relevance to humans. For example, zebrafish have tiny eyes, much smaller than humans. And, retinal organoids are not fully developed retinas nor are they part of a complete eye system.
The Foundation is funding Martha Neuringer, PhD, Oregon Health & Science University, to develop a non-human primate model of USH1B, which, if successful, would closely resemble humans with USH1B. That work is in progress.
David Williams, PhD, University of California Los Angeles, Jacque Duncan, MD, University of California San Francisco, and Joseph Carroll, PhD, Medical College of Wisconsin are collaboratively developing a pig model of USH1B which also has the potential to closely resemble the human disease. That work is also in progress.
The animal models under development will help researchers learn more about the development of USH1B and its effect on both vision and hearing, as well as provide a higher species animal model for the testing of potential therapeutics.
Large size of MYO7A gene: Adeno-associated viruses (AAVs) are the gene delivery systems commonly used in emerging gene augmentation therapies, as well as in the FDA-approved retinal gene therapy, LUXTURNA. AAVs have a cargo capacity of 4.7 kb. However, the MYO7A gene is 6.6 kb, so standard AAV systems won’t work. Atsena Therapeutics and TIGEM are currently developing dual vector AAVs to deliver MYO7A in two containers (more on these approaches below), which would facilitate the delivery of the larger transgene size.
Natural history and clinical trial endpoints: While some natural history studies have been conducted for USH1B, more knowledge is needed about the rate and nature of disease progression so that researchers can understand the best windows for treatment and which outcome measures will be optimal for clinical trials of emerging therapies.
Mark Pennesi, MD, PhD, Oregon Health & Science University, said that the clinical research community needs to work closely with the FDA to identify endpoints that are better suited for clinical trials of therapies for Usher syndrome and related conditions.
Dual vector gene therapies: To overcome the challenge of delivering the large MYO7A gene into retinal cells via gene augmentation therapy, both Alberto Auricchio, MD, at the Telethon Institute of Genetics and Medicine (TIGEM), and Shannon Boye, PhD, of Atsena Therapeutics and University of Florida, presented their dual-AAV vector approaches for delivering the MYO7A gene to retinal cells. Both of these approaches involve delivery of the gene in two containers — the front half in one container and the back half in another. When the two halves arrive in the cells, they join together through a natural process called homologous recombination to make the full-length gene so that the full-length protein can be produced.
AAVantgarde Bio, co-founded by Dr. Auricchio, is planning to begin enrollment for a Phase 1/2 clinical trial of their dual-vector approach for USH1B in April 2022.
Atsena Therapeutics, co-founded by Dr. Boye and funded through the Foundation’s RD Fund, has made significant progress in developing a safe and effective dual vector AAV therapy, having evaluated dozens of different constructs. The company is close to selecting a lead candidate, and from there will move into IND-enabling studies for launching a clinical trial.
Dr. Boye noted that while both companies are developing dual-vector gene therapy approaches which apply homologous recombination, they are technically different.
Dr. Boye added, “Alberto and I have known each other for a long time and we both see the value of collaborating in a precompetitive space. It’s what helps get these treatments over the finish line more quickly.”
While the Foundation is focused on emerging therapies that directly address USH1B, we are also encouraged by the progress being made in our investments in gene-agnostic approaches, like those from Nacuity and SparingVision, which are in, or approaching, clinical trials.
NACA small molecule: Nacuity Pharmaceuticals’ Halden Conner, MBA, and Jami Kern, MBA, PhD, reviewed the Phase 1/2 clinical trial in Australia for the antioxidative molecule NACA being developed by their company. Initiated in January 2020, the 24-month study is enrolling 48 participants with Usher syndrome (all forms). The company will report six-month results in the last quarter of 2021 and 12- and 18-month results in 2022. A clinical trial for retinitis pigmentosa is planned in the US and Australia in 2022.
The oral, gene-agnostic drug is designed to slow vision loss by reducing oxidative stress.
Headquartered in Dallas, Nacuity is funded through the Foundation’s RD Fund.
“While the Foundation is focused on emerging therapies that directly address USH1B, we are also encouraged by the progress being made in our investments in gene-agnostic approaches, like those from Nacuity and SparingVision, which are in, or approaching, clinical trials,” said Benjamin Yerxa, PhD, the Foundation’s chief executive officer. “These have the potential to preserve vision for a broad range of retinal disease patients, including those with USH1B.”