1. X-linked retinoschisis (XLRS) gene therapy clinical trial. XLRS is a genetic disease caused by mutations in the retinoschisin (RS1) gene. An absent or mutated RS1 protein in the retina of patients with XLRS leads to abnormalities in the normal laminar structure of the retina, resulting in impaired visual acuity and increased propensity to retinal detachment. In collaboration with Dr. Paul Sieving's group, we have developed and optimized a self-complementary AAV vector that is capable of mediating stable and retinal specific expression of human RS1 protein. To meet the FDA requirements for gene therapy clinical trials, we have completed a preclinical efficacy study in a retinoschisin knockout mouse model, and a vector toxicology study in both mouse and rabbit models. The investigative new drug application has been approved by FDA, and a Phase I/II clinical trial has started. A total of nine patients with XLRS will receive (or have received) the vector administration in year 2015. 2. Preclinical gene therapy studies for retinitis pigmentosa due to RPGR or RP2 mutations. X-linked forms of retinitis pigmentosa (XLRP) are relatively severe blinding disorders, resulting from progressive photoreceptor dysfunction primarily caused by mutations in RPGR or RP2 gene. Gene therapy for RPGR-XLRP has been hampered by the relatively slow disease progression in mouse models and by difficulties in cloning the RPGR-ORF15 cDNA that includes a purine-rich 3-coding region. We managed to overcome these problems and have generated AAV vectors carrying full-length mouse and human RPGR ORF15 coding sequences. We have also developed a self-complementary AAV vector carrying human RP2 expression cassette. We have completed long-term (18-24 months) dose efficacy/toxicity studies in mouse models with RPGR or RP2 deficiency. Our results demonstrate that administration of the RPGR AAV vectors at appropriate doses can significantly preserve the retinal function and delay the photoreceptor loss in the mice with RPGR deficiency. Additionally, administration of the RP2 vector with a broad dose range can remarkable maintain the function and viability of cone photoreceptors in the mice with RP2 deficiency. In order to bring the therapies to the clinic, we are currently optimizing the vectors and testing them in mice with different background/mutations. 3. Gene therapy for Leber congenital amaurosis due to CEP290 mutations. Leber congenital amaurosis (LCA) is one of the most common causes of blindness in children. People with this disease typically have severe visual impairment beginning in infancy. Mutations in the CEP290 gene account for 20-25 percent of LCA, afflicting an estimated 20,000 people worldwide. Since the size of CEP290 coding sequence (7.4 kb) exceeds the packaging limit of AAV vector (5kb), we are seeking several approaches including the use of dual-vector and functional subunit of CEP290 to deliver the therapeutic genes into the retina. We have made a series of AAV vectors and have tested them on a mouse model with Cep290 mutation. We recently identified one vector that is capable of preserving the retinal function and structure in the mouse model. A detailed study is being conducted. 4. Application of CRISPR for treating retinal degenerative diseases. We have recently initiated a new project involving the use of CRISPR technology to knockdown dominant gene mutations in the retina. We are hoping that we can develop the CRISPR technique into a treatment for autosomal dominant retinal diseases.
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