A novel cell-cycle dependent replicating AAV platform for neonatal inborn errors of metabolism summary inborn errors of metabolism (IEMS), such as methylmalonic acidemia (MMA) and hereditary…

The National Institutes of Health National Center for Advancing Translational Sciences awarded $306,872 to Endless Vectors Bioscience on September 3, 2026, under the NCATS Program (CFDA 93.350) to develop and validate a cell cycle-dependent replicating adeno-associated virus platform for treating neonatal inborn errors of metabolism.

Endless Vectors will assess tissue-specific replication, episomal persistence, and long-term safety and efficacy of the CCRAAV platform in neonatal mouse liver models. The technology addresses mitotic dilution limitations of conventional recombinant AAV vectors in proliferating tissues by using scaffold/matrix attachment regions for nuclear tethering and replication initiation regions to sustain episomal replication alongside host cell division, maintaining long-term gene expression in growing organs. Preliminary studies demonstrate retention of 1–2.5 genome copies per cell and greater than 10 percent reporter-positive cells after approximately 60 cell doublings, compared to near-complete loss with standard AAV. This Phase I SBIR project aims to establish proof-of-concept for a low-dose, durable, and safe gene therapy platform applicable to metabolic disorders including methylmalonic acidemia and hereditary tyrosinemia type 1.

Performance occurs in Cambridge, Massachusetts, with a period of performance from September 3, 2026, through August 31, 2027.

A novel cell-cycle dependent replicating AAV platform for neonatal inborn errors of metabolism summary inborn errors of metabolism (IEMS), such as methylmalonic acidemia (MMA) and hereditary tyrosinemia type 1 (HT1), are life-threatening pediatric disorders that require durable gene therapies to correct underlying metabolic defects. Recombinant adeno-associated virus (RAAV) vectors, despite their favorable safety profile and broad tropism, are limited by mitotic dilution in proliferating tissues, reducing long-term efficacy in growing organs. High-dose RAAV can partially offset the mitotic loss but carries risks of hepatotoxicity and insertional mutagenesis, while novel capsid engineering remains in early development. To overcome these limitations, we propose a cell cycle-dependent replicating AAV (CCRAAV) platform that maintains episomes in dividing cells by using scaffold/matrix attachment regions (S/MARS) for nuclear tethering and replication initiation regions (IRS) to recruit host replication machinery, enabling episomes to replicate with the host cell and sustain long-term expression. Preliminary studies show that CCRAAV vectors retain 1-2.5 genome copies per cell and >10% reporter-positive cells after ~60 doublings in HEK293T cells, in sharp contrast to near-complete loss with conventional RAAV. This phase I sbir project will assess CCRAAV's tissue-specific replication, episomal persistence, and long-term safety and efficacy in neonatal mouse liver, establishing proof-of-concept for a low-dose, durable, and safe gene therapy platform. Successful completion will overcome key limitations of RAAV and enable transformative therapies for IEMS.