Lipodystrophy includes a heterogeneous group of disorders that are characterized by abnormal ordegenerative conditions of the adipose tissue. This rare and often underdiagnosed condition can bepartial/localized or generalized and is generally associated with metabolic disorders such as insulinresistance, diabetes, hyperglycemia, hyperlipidemia, and other severe conditions. Lipodystrophy can becongenital or acquired and can often lead to deadly consequences due to liver, kidney, and cardiaccomplications. All forms of lipodystrophy have severe insulin resistance and very low leptin levels. Currently,leptin replacement using Metreleptin is the only treatment of lipodystrophy. However, Metreleptin injectionsat a dose of once or twice a day cost an average of $565,000 per patient/year and can have adverse sideeffects. Zvelt therapeutics is developing a safe, efficient, and cost-effective therapy for the treatmentof lipodystrophy. This therapy is mediated by recombinant adeno-associated virus (rAAV) vectors that offerlong-lasting transgenic expression and low immunogenicity. Typically, when AAV therapies are deliveredsystemically, 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 attaintherapeutic benefits. To overcome these challenges, Zvelt will use a novel engineered AAV serotypeRec2 that preferentially targets fat, coupled with a dual cassette platform that minimizes transgeneexpression in the liver. Zvelt Therapeutics has already established the proof of efficacy of the Rec2/DualCassette vector containing the leptin gene (Rec2-leptin) for correcting leptin deficiency, obesity, andmetabolic syndromes in mouse models. Zvelt's platform has been demonstrated to express in the targetedadipose tissue while restricting off-target expression in the liver in the mouse model. In this STTR Phase Iproject, we will perform dose-finding and safety analyses of Rec2-Leptin in relevant lipodystrophy mousemodels towards validation of this innovation for the effective treatment of lipodystrophy.In Phase II, we will address key technical aspects of product development and safety and efficacy studies inlarger animal models to obtain essential data to support IND application. This will pave the way for a first-in-human clinical study to collect evidence on the safety and efficacy of the treatment for lipodystrophy.
Public Health Relevance Statement: NARRATIVE
Lipodystrophy, a rare and usually underdiagnosed condition that affects adipose tissues and manifests in
various metabolic disorders has no definitive cure, with existing ones being costly and causing several
adverse effects. Zvelt Therapeutics has developed an engineered AAV serotype coupled with dual cassette
(Rec2/dual cassette) capable of specifically targeting adipose tissues and avoiding the liver, thus
making it a safe and cost-effective treatment for lipodystrophy. This STTR project will focus on preclinical
validation of the dosage and safety of this novel therapy in a murine model.
Project Terms:
