Targeted Treatments for Inherited Neuromuscular Diseases of Childhood.

In the past decade, the number of genes linked to neuromuscular diseases of childhood has expanded dramatically, and this genetic information is forming the basis for gene-specific and even mutation-specific therapies. At the forefront of these advances are the two recently approved treatments for spinal muscular atrophy: one, an antisense oligonucleotide that modifies splicing of the SMN2 gene, and, the other, a gene therapy vector that delivers the SMN1 gene to motor neurons, both of which are allowing patients to acquire developmental milestones previously unseen in this fatal disease. This review highlights these advances and emerging targeted therapies for Duchenne muscular dystrophy and centronuclear myopathy, while also covering enzyme replacement therapy and small molecule-based targeted therapies for conditions such as Pompe's disease and congenital myasthenic syndromes. With these and other newer techniques for targeted correction of genetic defects, such as CRISPR/Cas9, there is now hope that treatments for many more genetic diseases of the nervous system will follow in the near future.

Nusinersen: A Novel Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) encompasses a group of autosomal recessively inherited degenerative neuromuscular disorders. They range in severity from neonatal onset with rapidly progressive weakness and early mortality (SMA-1), to onset in infancy (SMA-2), to adolescent/adult onset with indolent clinical course (SMA-3/-4). SMA patients share mutations in the survival motor neuron (SMN) gene; variations in clinical phenotypes are attributable to copy numbers of the closely related SMN2 gene. In December 2016, the US Food and Drug Administration (FDA) approved nusinersen (Spinraza, Biogen, Cambridge, MA) to treat SMA. Nusinersen, an antisense oligonucleotide, is administered directly into cerebrospinal fluid. It alters SMN2 pre-RNA splicing so exon 7 is included, increasing expression of functional SMN protein. Although nusinersen was FDA approved for treatment of all forms of SMA, the initial clinical trials were limited to patients up to age 14 years, diagnosed with SMA-1,-2, -3, not on mechanical ventilation support. Two subsequent phase 3 trials were completed for SMA-1 and SMA-2/-3 and demonstrated improved motor milestones and event-free survival, better than expected based on natural history studies. Efficacy assessments for patients receiving nusinersen are based on serial assessments of performance on age-appropriate standardized motor scales. Treatment requires complex financial and logistics because of the very high drug cost, intrathecal administration, and medical fragility of the patients. Treatment implementation also engenders ethical considerations related to cost, insurance coverage, limited clinical data on groups of patients not in clinical trials, and questions of duration of treatment. Nusinersen has been integrated into the treatment of many SMA patients.