Inherited retinal dystrophies (IRDs) are a group of genetically and clinically heterogeneous disorders caused by progressive degeneration of photoreceptor (PR) rods, cones, or both. The majority of IRDs are characterized by retinal degeneration, which can lead to significant vision impairment and blindness and are thus serious and debilitating conditions. Most IRDs have no treatment options.
Stargardt disease (STGD1) is an autosomal recessive IRD that generally manifests during childhood or early adulthood. It has an estimated prevalence of 1 in 8,000 to 10,000 patients. STGD1 is due to mutations in the adenosine triphosphate (ATP)-binding cassette, sub-family A, member 4 (ABCA4) gene. The ABCA4 protein is an ATP-binding cassette (ABC) transporter expressed in PR outer segments in both rods and cones. This protein plays a critical role in the visual phototransduction cycle. Mutations in the ABCA4 gene adversely affect the metabolism of vitamin A, leading to deposition and build-up of lipofuscin containing bisretinoid toxins, such as N-retinylidene-N-retinylethanolamine (A2E), in the PRs and retinal pigment epithelium (RPE) cells. This accumulation of lipofuscin causes the formation of yellowish flecks over the macula and toxins such as A2E lead to oxidative stress and death of RPE cells and light-sensing photoreceptors.
Gene therapies are emerging as potentially viable treatments for a variety of IRDs. Many of these therapies are based on the use of adeno-associated virus (AAV) vectors containing DNA that encodes a functional gene to replace a defective gene.
Although AAV vectors have good biological characteristics (i.e., high transduction efficiency, genetic stability) and acceptable safety profiles (non-immunogenic, non-pathogenic, few serious adverse effects), one drawback is its packaging capability. Until recently, use of AAV vectors was not considered appropriate for STGD1 gene therapies since the ABCA4 gene is too large and exceeds the capacity of AAV vectors. However, SpliceBio, a genetic medicines company, has developed a proprietary protein splicing intein platform using dual AAV vectors that enables the delivery of genes too large for conventional AAV vector systems. SpliceBio is using this technology to develop a genetic treatment for STGD1.
SB-007 is a new gene therapy investigational medicinal product based on dual AAV8 gene delivery for the full-length reconstitution of the ABCA4 protein inside the target cell using protein trans-splicing mediated by small polypeptidic proprietary sequences called split-inteins. While each alone are inactive, the co-expression of the 2 vectors is expected to lead to highly efficient PTS and reconstitution of the full-length biologically active ABCA4 protein in target photoreceptor cells. Further, SB-007 is anticipated to enable long-term expression of a functional wild type ABCA4 protein in the retina of patients and thus slow or blunt further vision loss after a single subretinal administration.
First-in-human trials are conducted primarily to determine the safe dose range for further clinical development of promising drug candidates. This first-in-human study is being conducted to identify doses of SB-007 that are safe and demonstrate a potential efficacy signal in subjects with moderate or advanced STGD1.
