Novel Adipose Targeted Gene Therapy for Lipodystrophy

PROJECT SUMMARY Lipodystrophy includes a heterogeneous group of disorders that are characterized by abnormal or degenerative conditions of the adipose tissue. This rare and often underdiagnosed condition can be partial/localized or generalized and is typically associated with metabolic disorders such as insulin resistance, diabetes, hyperglycemia, hyperlipidemia, and other severe conditions. Lipodystrophy can be congenital or acquired and can often lead to deadly consequences due to liver, kidney, and cardiac complications. All forms of lipodystrophy have severe insulin resistance and very low leptin levels. Currently, leptin replacement using Metreleptin is the only approved and recommended treatment of lipodystrophy. However, metreleptin therapy poses several challenges including poor efficacy, adverse side effects, discomfort of use (1-2 injections per day), poor compliance and high costs exceeding $1.3 million per patient/year. Zvelt Therapeutics is developing a safe, efficient, and cost-effective therapy for the treatment of lipodystrophy with long-lasting effectiveness of at least 5 years. The therapeutic injection, priced at approximately $2M will significantly reduce the lipodystrophy treatment cost per patient/year by at least 70%. The therapy is mediated by recombinant adeno-associated virus (rAAV) vectors that offer long-lasting transgenic expression and low immunogenicity. Typically, when AAV therapies are delivered systemically, the vast majority of AAVs are sequestered in the liver, with little expression in target tissues. This effect causes a narrow therapeutic window, as systemic AAV must be dosed near toxic levels to attain therapeutic benefits. To overcome these challenges, Zvelt has developed Rec2-leptin/dual cassette, an AAV based leptin gene therapy for the treatment of lipodystrophy that preferentially targets fat cells/adipose tissue while restricting transgene expression in the liver. In previous STTR Phase I, we have already demonstrated that a single intraperitoneal (IP) injection of Rec2-Leptin/dual cassette in ob/ob mice (murine model of lipodystrophy) can normalize the metabolic syndromes without adverse effects even at the lowest dose tested (1E9 vg/mouse) and the transgene (leptin) expression was restricted to the targeting tissue - visceral fat and not in the liver. In this STTR Phase II, we will determine minimum Effective Dose (MED), establish safety and delivery route [IP vs subcutaneous (SC)] and efficacy of Rec2-Leptin/dual cassette in aP2-nSREBP1c transgenic mice (second murine model of lipodystrophy). Additionally, anti-Rec2 neutralizing antibody assay will be standardised for both mouse and the non-human primate (NHP). Subsequently, the safety of different delivery routes and doses and durability of efficacy of Rec2-leptin/dual cassette will be evaluated in African green monkeys. The preclinical results of Phase II will contribute towards the pre-IND meeting with the FDA. Based on the feedback from the agency, we will conduct a GLP toxicology study in wild type mice, using the same drug product that was used in our NHP studies. We will then produce GMP drug and file an IND to conduct a Phase I/II trial in lipodystrophy patients.