Gene Therapy2019-04-16T00:48:21+00:00

GENE THERAPY

GENE THERAPY

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
eye photoreceptors

Source: Current Stem Cell Reports. June 2015, Volume 1, Issue 2, pp 79-99.

Retina:

  • 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:

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.

Rhodopsin Molecule

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

Proof-of-Concept: Preservation of Retinal Structure and Function in Naturally Occurring RHO Mutant Dogs

Anatomy and Function

Source: PNAS September 4, 2018 115 (36) E8547-E8556
White bar indicates the thickness of the photoreceptors, the cells that perceive light in the retina and are required for vision.

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 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.

Gene Therapy: Resolution of Retinal Microdetachment in Naturally Occurring Canine Disease Model

Source: Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):E2839-E2848.

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.