388. Wide-Scale Gene Transfer of Amyotrophic Lateral Sclerosis Related Proteins To Adult Rats

Wide-scale gene transfer to the central nervous system (CNS) has been achieved in the past few years by way of a peripheral route of administration. This may be relevant to gene therapy considering that a one-time peripheral treatment can penetrate the CNS and affect CNS function long-term. We have used the wide-scale approach to study a disease of the spinal cord, amyotrophic lateral sclerosis (ALS). TDP-43 and FUS are RNA-binding proteins involved in the genetics and pathology of ALS and frontotemporal lobar degeneration (FTLD). Most cases of ALS, including sporadic, non-familial ALS, harbor TDP-43 pathology. TDP-43 was previously expressed in the spinal cord among other tissues after an intravenous delivery of AAV9 to neonatal rats. An adult onset model would be more relevant to ALS and more amenable for sequential gene therapy or pharmacological interventions. In this study, we attempted to induce motor paralysis relevant to ALS in adult rats by expressing TDP-43 or FUS. Several AAV vectors encoding GFP were tested for optimization, AAV8, 9, and 10. The vectors were applied via tail vein to young rats (6 weeks old) at an equal per kg vector dose. Gene transfer in the adult rat CNS was feasible and highly neuron-selective as observed in the spinal cord and the cerebellum with all AAVs tested. When TDP-43 or FUS were individually expressed in adults with AAV9, both proteins caused severe immobilization within 4 weeks, and in the case of FUS, there was physical atrophy. With refinement, this approach could yield an appropriate platform for studying the mechanisms and molecular therapy of ALS and FTLD.