“Developing Novel Gene Therapy Technology to Treat Orphan Inherited Retinal Diseases.”
Eye: The ideal organ for gene therapy
- Direct access to the target tissue: minimizing systemic exposure
- Tissue specific vectors/promotors: limiting off-target expression
- Relatively immune privileged: reducing the risk of inflammation
- Most orphan inherited retinal diseases are due to genetic disorders
- More than 250 retinal disease genes have been identified and mapped
- Only one FDA/EMA approved gene therapy for retinal diseases is currently available
Gene therapy is a technology that seeks to correct a faulty gene by providing a healthy gene replacement, through a single treatment, leading to the expression of a therapeutic protein that was otherwise not being produced.
Adeno-Associated Virus (AAV Vector)
We are particularly interested in adeno-associated virus (AAV) gene therapy delivery vehicles. AAV vectors have a well-documented safety record for gene delivery in the eye, targeting specific cells of interest, thereby minimizing off-target side effects.
Mutation Independent Strategy
Orphan inherited retinal diseases are generally caused by many different mutations within a single gene. Our strategy is to develop mutation independent treatment options to potentially treat the entire class of a disease.
RHO-adRP (AAV Vector)
Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP), the most common autosomal dominant retinal disease, is an orphan monogenic inherited retinal disease that is characterized by progressive and severe loss of vision leading to blindness in both eyes.
We estimate that there are approximately 11,000 RHO-adRP individuals on a combined basis in the United States and the five major European markets.
Rhodopsin is a light-sensitive protein in the rod photoreceptors in the eye. In rhodopsin mediated adRP, mutations in the Rhodopsin gene lead to production of a toxic protein and severe vision loss in patients over time. There is currently no FDA or EMA approved therapy to treat this orphan inherited retinal disease.
IC-100 is a mutation independent gene therapy, delivered by an AAV5 vector. It is designed to simultaneously knockdown the production of the patient’s toxic rhodopsin protein produced by the mutated gene and replace it with a healthy rhodopsin protein via a single vector.
Gene Therapy: Potential for a single treatment
Mutation Independent: More than 150 identified rhodopsin mutations
Single Vector Efficiency: Ability to knock down causative gene and deliver its replacement simultaneously
BEST1 (AAV Vector)
BEST1 Related Retinal Diseases
Best vitelliform macular dystrophy, an orphan inherited retinal disease also known as Best disease, is part of a group of diseases that are collectively referred to as bestrophinopathies which are believed to be caused by mutations in the BEST1 gene. These diseases generally affect individuals in both eyes.
We estimate that there are approximately 10,000 – 40,000 individuals in the United States and the five major European markets on a combined basis with Best disease.
The BEST1 gene encodes a multifunctional protein known as bestrophin1, or BEST1, that regulates ion transport and intracellular calcium signaling in retina cells and helps maintain homeostasis in the subretinal space between photoreceptors and the retinal pigment epithelial (RPE) cells. The lack of functional BEST1 protein results in the formation of microdetachments, followed by egg yolk-like lesions in the macula, center of the retina, which over time progress to macular atrophy and loss of central vision. There is currently no FDA or EMA approved therapy to treat this orphan inherited retinal disease or other bestrophinopathies.
IC-200 is a mutation independent gene therapy, delivered by an AAV2 vector. It is designed to deliver the BEST1 gene to RPE cells to produce BEST1 protein and potentially normalize the homeostasis in the subretinal space between the photoreceptors and RPE cells and restore vision in patients with retinal diseases due to BEST1 mutation.
Lebers Congenital Amaurosis (LCA10) Due to CEP290 Mutations
Lebers Congenital Amaurosis type 10 (LCA10), the most common type of LCA, is an orphan inherited retinal disease caused by mutations in the CEP290 gene. Mutations in CEP290 lead to severe bilateral vision loss in early childhood, incapacitating affected individuals.
We estimate that there are approximately 2,700 to 4,100 individuals in the United States and the five major European markets on a combined basis with LCA10.
The size of the CEP290 gene exceeds the packaging capacity of standard AAV vectors. The innovative mutation independent minigene strategy allows the use of a smaller sized CEP290 gene that not only fits inside the AAV vector but also transcribes a functional protein. There is currently no FDA or EMA approved therapy to treat LCA10.
We are developing a mutation independent AAV minigene therapy designed to a deliver miniCEP290 gene to cone photoreceptors to restore vision in patients with LCA10.
Autosomal Recessive Stargardt Disease (STGD1) Due to ABCA4 Mutations
Stargardt disease, the most common inherited macular dystrophy in both children and adults, is an orphan inherited retinal disease that leads to the macular atrophy and loss of vision.
We estimate that there are approximately 62,000 to 77,000 individuals in the United States and the five major European markets on a combined basis with Stargardt disease.
The most common type of Stargardt disease is inherited in the autosomal recessive form, which is referred to as STGD1. STGD1 is caused by mutations in the ATP-binding cassette, subfamily A, number 4, or ABCA4 gene, which is responsible for making a protein that helps to clear byproducts resulting from the visual cycle from inside photoreceptor cells in the eye.
The size of the ABCA4 gene exceeds the packaging capacity of standard AAV vectors. The innovative mutation independent minigene strategy potentially allows the use of a smaller sized ABCA4 gene that not only fits inside the AAV vector but also transcribes the functional protein. There is currently no FDA or EMA approved therapy to treat autosomal recessive Stargardt disease.
We are developing a mutation independent AAV minigene therapy designed to a deliver miniABCA4 gene to photoreceptors to restore vision in patients with Stargardt disease.
Usher Syndrome Type H2A
USH2A-related inherited retinal diseases are a group of orphan IRDs associated with mutations to the USH2A gene. The USH2A gene encodes a protein, usherin, which is believed to be important in the development and maintenance of cells in the retina and the inner ear. USH2A-related IRDs include retinitis pigmentosa associated with Usher syndrome type 2A and USH2A-associated nonsyndromatic autosomal recessive retinitis pigmentosa. Usher syndrome type 2a is an autosomal recessive genetic condition characterized by hearing loss from birth and progressive vision loss, due to retinitis pigmentosa, that begins in adolescence or adulthood. USH2A-associated nonsyndromatic autosomal recessive retinitis pigmentosa is a genetic condition that manifests as vision loss without associated hearing loss. There is no FDA or EMA approved therapy to treat USH2A.
We are seeking to treat vision loss associated with what is reported as the most common form of autosomal dominant retinitis pigmentosa (rhodopsin-mediated) and the most common form of autosomal recessive of retinitis pigmentosa (USH2A-related). Retinitis pigmentosa is the most common orphan IRD.
Usher syndrome type 2A: Prevalence estimates range between ~13,000-55,000 in US + EU5 based on published literature
USH2A related nonsyndromatic autosomal recessive retinitis pigmentosa: Prevalence estimate of ~7,000 in US + EU5 based on published literature