Big News! 2020 Award Announcement
Grant Recipient
We are so excited to share with you that Martha Neuringer’s program at OHSU Casey Eye Institute is the recipient of Save Sight Now’s 2019 Grant. The $285,000 grant will continue funding the development of genetic engineering tools needed to create a Non-Human Primate (NHP) model of an inherited retinal disease. This program seeks to create an accurate model of Usher Syndrome Type 1B in non-human primates, confirm how closely it resembles the human disease, and use the model to test a new type of Dual-AAV gene therapy.
Our grant will help sustain this program for up to three years; and it’s because of the support and generosity of our 1,105 donors. Their donations will translate into significant impact helping thousands of Usher Syndrome children and adults who are rapidly losing their vision. The innovative gene editing work being created and tested in this program will also have far-reaching impact that goes beyond Usher Syndrome and other retinal disorders.
“This project achieves both the creation of a necessary accurate animal model of USH1B using gene editing tools AND supports a new large gene therapeutic approach for treating a disease.”
Martha Neuringer Ph.D. and Shannon Boye Ph.D.
Why This Program Is So Significant
The Foundation Fighting Blindness Scientific Advisory Board highly recommended supporting Dr. Neuringer and her team to generate an Usher 1B animal model, noting that “successful production of an NHP (Non-Human Primate) model of USH1B with a retinal disorder will immediately trigger more Usher Syndrome studies aimed at correcting the disease.” It is important to note that while the goal of this project is to generate an accurate animal model for Usher Syndrome, the project also plans on testing Dr. Shannon Boye’s dual-AAV gene therapy strategy. This project achieves both the creation of a necessary accurate animal model of USH1B using gene editing tools AND supports a new large gene therapeutic approach for treating a disease.
genetically targeting Ush1B’s two major hurdles:
There is no accurate animal model for testing USH1B treatments
Currently it is only possible to test the safety and delivery of USH1B treatments in animal models, but not the effectiveness of the treatment as it relates to humans. Myosin VIIa – the gene responsible for causing USH1B in humans doesn’t play the same functional role within the retina of any known animals except primates. However, Usher Syndrome is not a naturally occurring disorder within primates. So, Martha Neuringer’s team at OHSU is using a CRISPR gene editing technique to alter the Myosin VIIa gene in primate embryos in order to create an animal model that accurately expresses the Usher Syndrome 1B phenotype (symptoms) from birth.
An USH1B genetic treatment has no delivery system
In order to deliver a corrected gene (“treatment package”) you need a delivery system that is effective at infecting cells – like a virus, but without its pathogenicity. USH1B is a large gene – too large to deliver using the current gold standard and only proven gene augmentation delivery system approved by the FDA - a Single-AAV (adeno-associated virus). Dr. Boye’s strategy uses a new Dual-AAV delivery system which attempts to solve the size issue by splitting the gene in two parts and delivering them separately. The two halves then reconstitute within the retina to form a whole properly functioning gene.
Overview
Proven system / ush1b problems / Proposed Solution
Medical Impact Beyond Usher Syndrome
Myosin VIIa - the gene associated with Usher Syndrome Type 1B has two major gene editing hurdles that are relevant to other ocular genetic diseases and beyond: it’s too large for current gene editing tools and there is no existing ideal animal model that accurately expresses the disease phenotype for testing pre-clinical treatments . Many other Usher Syndrome types like USH2A and USH1F also have a large gene problem, and lack a good animal model for testing as well. These two significant challenges aren’t only common in ocular genetic disorders, but also many other neurological and hematological diseases. Martha Neuringer’s innovative strategy is attempting to use CRISPR-cas9 (gene editing tool) to alter the DNA (Myosin VIIa gene) of a NHP (Non-human primate) embryo in order to create an ideal animal model from birth that accurately expresses the same disease symptoms as seen in humans. The gene editing tools and processes her team are creating - if successful - will theoretically be repeatable for any disease in need of an accurate animal model.
Shannons Boye’s Dual-AAV strategy is an attempt to overcome the large gene delivery hurdle. Her methodology proposes cutting the gene at an ideal location in order to create two small packages for easier delivery within a new hybrid AAV vector. Once administered to the retina the two halves of the gene recombine to form a whole functioning gene and ideally halting retinal degeneration. If this methodology is successful it lays the foundation for a reproducible blueprint for delivering any large gene that causes retinal disorders and theoretically for any other genetic disease with a large gene obstacle.
Pushing Forward
Even though this program holds incredible promise our work is far from over. The successful editing and birth of a genetically engineered USH1B model is difficult (to say the least) and has yet to be demonstrated, and the Dual-AAV strategy still has to be proven before even preparing for clinical trials. Clinical trials are incredibly expensive and this work is never guaranteed. Anyone who has Usher Syndrome Type 1B or any family member with a loved one who has USH1B knows the reality and pain of a failed clinical trial because of the unsuccessful 2017 UshStat trial. Usher Syndrome researchers learned a lot from that trial, but it serves as a constant reminder that we can’t count on one therapeutic strategy. We have to constantly be identifying and supporting new strategies and research programs in order to ensure we’ll find a valid treatment in time.
What’s next
We raised $285K in our first year. We originally had a goal of $2 million in 2 years, but COVID-19 has drastically impacted our ability to fundraise and significantly slowed research. We have a long way to go to hit our goal, but we are hopeful we can raise enough funding this year to make another substantial contribution to medical research. At the end of this year the process of selecting the most promising USH1B and Retinitis Pigmentosa research programs will begin again. In February 2021 The Foundation Fighting Blindness Scientific Advisory Board will begin a thorough 4 month long grant review process in order to identify the research team that has the greatest potential for therapeutic success; and that’s who we’ll be supporting.
Thank You
We can’t depend on pharmaceutical companies or the NIH to fund rare disease research for disorders like Usher Syndrome, that burden falls on the shoulders of parent lead organizations like Save Sight Now. This past year we asked for your support in sharing that burden, and you did, in a big way. Thank you to all of our family, friends, friends-of-friends and strangers who supported us, trusted us and donated. We are humbled by your generosity and we are so incredibly grateful for your support. We hope you continue to believe in us and our mission because we cannot do this without you.
Thank you to everyone we have worked with at the Foundation Fighting Blindness, you are the most reliable and informed partner we could have hoped for.