New Study - ALS Gene Therapy in Astrocytes enables re-innervation and improves muscles

Avrion CSO Dr. Bernard Schneider authors a new study demonstrating the potent effects of specifically targeting disease causing SOD1 by gene therapy in the astrocytes of a mouse model of the motor neuron disease ALS. The study shows that specifically targeting SOD1 in this cell type enables plasticity and re-innervation, increasing the number and activity of neuromuscular junctions, the essential connections between motor neurons and muscles, thereby allowing the preservation of muscle function. The data from this study have been incorporated in the design of AVR-001, Avrion's first gene therapy product aimed to treat ALS.
Expression of a miRNA targeting mutated SOD1 in astrocytes induces motoneuron plasticity and improves neuromuscular function in ALS mice
C. Rochat, N. Bernard-Marissal, S. Pradervand, F.E. Perrin, C. Raoul, P. Aebischer and B.L. Schneider.

In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell-autonomous and non-cell-autonomous mechanisms lead to the selective degeneration of motoneurons. Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1G93A protein. An AAV-gfaABC1D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of fast-fatigable motoneurons until disease end stage. In the gastrocnemius muscle of the treated SOD1G93A mice, the fast-twitch type IIb muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/re-innervation events. The transcriptome profiling of spinal cord motoneurons shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes provides therapeutic effects enhancing motoneuron plasticity and improving neuromuscular function in ALS mice.

Read the full manuscript here.