Motor neuron inhibition-based gene therapy for spasticity

Abstract

Spasticity is a condition resulting from excess motor neuron excitation, leading to involuntary muscle contraction in response to increased velocity of movement, for which there is currently no cure. Existing symptomatic therapies face a variety of limitations. The extent of relief that can be delivered by ablative techniques such as rhizotomy is limited by the potential for sensory denervation. Pharmacological approaches, including intrathecal baclofen, can be undermined by tolerance. One potential new approach to the treatment of spasticity is the control of neuromuscular overactivity through the delivery of genes capable of inducing synaptic inhibition. A variety of experiments in cell culture and animal models have demonstrated the ability of neural gene transfer to inhibit neuronal activity and suppress transmission. Similarly, enthusiasm for the application of gene therapy to neurodegenerative diseases of motor neurons has led to the development of a variety of strategies for motor neuron gene delivery. In this review, we discuss the limitations of existing spasticity therapies, the feasibility of motor neuron inhibition as a gene-based treatment for spasticity, potential inhibitory transgene candidates, strategies for control of transgene expression, and applicable motor neuron gene targeting strategies. Finally, we discuss future directions and the potential for gene-based motor neuron inhibition in therapeutic clinical trials to serve as an effective treatment modality for spasticity, either in conjunction with or as a replacement for presently available therapies.