Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases

There are several incurable diseases of motor neuron degeneration, includin g amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, hereditar y spastic hemiplegia, spinal muscular atrophy, and bulbospinal atrophy. Adv ances in gene transfer techniques coupled with new insights into molecular pathology have opened promising avenues for gene therapy aimed at halting d isease progression. Nonviral preparations and recombinant adenoviruses, ade no-associated viruses, herpesviruses, and lentiviruses may ultimately trans duce sufficient numbers of cerebral, brainstem, and spinal cord neurons for therapeutic applications. This could be accomplished by direct injection, transduction of lower motor neurons via retrograde transport after intramus cular injection, or cell-based therapies. Studies using transgenic mice exp ressing mutant superoxide dismutase 1 (SOD1), a model for one form of ALS, established that several proteins were neuroprotective, including calbindin , bcl-2, and growth factors. These same molecules promoted neuronal surviva l in other injury models, suggesting general applicability to all forms of ALS. Potentially correctable genetic lesions have also been identified for hereditary spastic hemiplegia, bulbospinal atrophy, and spinal muscular atr ophy. Finally, it may be possible to repopulate lost corticospinal and lowe r motor neurons by transplanting stem cells or stimulating native progenito r populations. The challenge ahead is to translate these basic science brea kthroughs into workable clinical practice.