ND Enabling Studies for CMT-101, a Novel Gene Therapy for Glycogen Storage Disease 1b

Cornela Therapeutics is a new startup company developing a novel AAV-based gene therapy to treat Glycogen Storage Disease lb (GSD-lb), a rare metabolic disease caused by mutations in the glucose-6- phosphate transporter gene (G6PT1, also known as SLC37A4). GSD-lb patients have a resulting deficiency in the G6PT1 enzyme, which converts glucose-6-phosphate into glucose; as a result, they cannot maintain normal blood-sugar levels between meals, leading to severe hypoglycemia and life-threatening hypoglycemic seizures. GSD-lb patients also experience neutropenia, which results in recurrent infections and a greater than 50% incidence of Inflammatory bowel disease (IBD). In the long term, cellular glycogen buildup can cause kidney and liver failure as well as liver cancer. Cornela's technology has been developed in the lab of Dr. Youngmok Lee at the University of Connecticut. Dr. Lee's research group has tested multiple iterations of an AAV-G6PT1 gene therapy, including an AAV construct featuring a liver-specific promoter. The liver-specific promoter showed better outcomes compared to previous constructs but was not able to fully rescue the GSD-lb mouse model. To achieve greater gene expression and full restoration of survival and metabolic parameters, Dr. Lee created a gene therapy vector driven by the native promoter of the human G6PT gene and further enhanced by transgene codon optimization. Preliminary results in the GSD-lb mouse model have demonstrated significant increases in gene expression, a remarkable increase in survival, and prevention of fasting-induced hypoglycemia, leading to normalized blood metabolites with enhanced durability. Cornela now seeks to advance the therapy, called CMT-101, into formal pre-clinical development via this Fast Track STTR proposal. In Phase I, we will conduct dose-finding and biodistribution studies, a Prelnvestigational New Drug (IND) meeting with FDA and then long-term dose finding/biodistribution studies and GLP toxicology studies in Phase II of the project. We have an interdisciplinary team of experts in preclinical GSD-lb research, clinical translation, and commercial development of AAV therapies for rare diseases. Cornela's regulatory and development path is informed by the development of GSD-la gene therapy, now in late-stage clinical studies; the AAV program for la employs the same vector serotype (AAVS) as our construct and the primary clinical outcome measures (fasting glucose levels) will be identical between the two programs. The results obtained from this STTR proposal will be leveraged in an IND application for clinical studies of CMT-101. Project Summary/Abstract