Targeting of Motor Neurons by AAV in a Large Animal Model

Rowan-Virtua School of Osteopathic Medicine leads a program of translational research focused on inherited pediatric leukodystrophies, with a principal emphasis on Canavan disease. Francis's laboratory applies a systems-based approach to characterize pathogenic mechanisms that underlie defective myelination and white matter degeneration, seeking targets for therapeutic intervention. Central to this work is the study of aspartoacylase (ASPA), an oligodendrocyte-specific enzyme required for catabolism of N-acetylaspartic acid (NAA). Loss of ASPA function produces an accumulation of NAA and consequent white matter pathology in rodent models that mirrors human Canavan disease. By delineating the spatio-temporal regulation of the NAA metabolic cycle during development in both normal and aspa-null rodents, Francis aims to identify key metabolic interactions between neurons and oligodendrocytes that are essential for postnatal myelination and cellular integrity.

The research program integrates molecular, biochemical, histological and behavioral analyses across scales, enabling extrapolation from discrete molecular observations to whole-animal phenotypes. Functional intervention is a core component of proof-of-principle studies: Francis's group employs viral vector-mediated gene delivery, particularly adeno-associated viral (AAV) vectors, to transduce neurons and deliver genes of interest in vivo. Representative work includes AAV-driven expression of reporter genes (GFP) to demonstrate efficient neuronal transduction and axonal transport from injection sites, and AAV-2-mediated delivery of aspartoacylase in tremor rat models. The laboratory also investigates immune responses to AAV in clinical and preclinical contexts, a critical consideration for translational gene therapies.

In parallel with gene therapy approaches, the lab advances cell transplantation strategies to replace or support oligodendrocytes. Studies using GFP-transgenic donor cells demonstrate successful engraftment in subcortical white matter and differentiation into oligodendrocyte-lineage cells, supporting combined cell- and gene-based therapeutic concepts. Dietary metabolic interventions also feature within the group's portfolio; for example, dietary triheptanoin was shown to rescue oligodendrocyte loss, dysmyelination and motor dysfunction in a mouse model, illustrating the laboratory's commitment to multimodal therapeutic exploration.

Francis's publication record documents contributions spanning basic mechanisms of aspartoacylase function, developmental regulation of myelination, translational gene therapy trials, and studies of immune responses to viral vectors. This body of work underscores an overarching translational goal: to move findings from mechanistic animal studies toward therapeutic strategies that preserve or restore white matter integrity in Canavan disease and related leukodystrophies. Methodologically diverse and clinically oriented, the Francis laboratory situates molecular discovery within an integrative framework that combines gene therapy, cell replacement, metabolic modulation, and comprehensive phenotypic analysis to address pediatric neurodegenerative disorders of myelin.