Drug treatment for spinal muscular atrophy types II and III

Abstract

BackgroundSpinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011. ObjectivesTo evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely. Search methodsWe searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials. Selection criteriaWe sought all randomised or quasi-randomised trials that examined the e icacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year a er the onset of treatment. Secondary outcome measures within one year a er the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period.Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review.

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics

“…Until recently no drug treatment had proved to be able to influence the disease course of SMA. A Cochrane review published in 2012 reported six randomized placebo-controlled trials on treatment for SMA using creatine, phenylbutyrate, gabapentin, thyrotropin-releasing hormone, hydroxyurea and combination therapy with valproate and acetyl-L-carnitine [36,37]. None of these studies showed statistically significant effects on the outcome measures in participants with SMA types 2 and 3.…”

Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy

“…Thus it has been proposed that preventing muscle atrophy could ameliorate the symptoms of muscle weakness in SMA patients [21]. Clinical trials with creatine, phenylbutryate, gabapentin and thyrotropin releasing hormone in type II and III SMA patients showed no significant effect on the disease course [22]. Delivery of follistatin, a negative regulator of muscle growth, improved the muscle mass but had no increase in maximium survival in SMA mice [23].…”

Therapy Development for Spinal Muscular Atrophy in SMN Independent Targets

“…The potential drugs include histone deacetylase (HDAC) inhibitors such as sodium butyrate [ 41 ], phenylbutyrate [ 42 ], valproic acid (VPA) [ 43 ], trichostatin A [ 44 ], SAHA [ 45 ], and LBH589 [ 46 ], as well as hydroxyuria [ 47 ], sodium vanadate [ 48 ], aclarubicin [ 49 ], indoprofen [ 50 ], bortezomib [ 51 ], and aminoglycosides, such as tobramycin, amikacin [ 52 ], TC007 [ 53 ], and G418 [ 54 ]. Since there are still no drugs that have shown consistent benefits in clinical trials [ 55 , 56 ], finding an effective treatment with distinct therapeutic mechanisms, such as SMN independent targets, is necessary for future SMA therapy.…”

“…However, another clinical trial which enrolled 120 type II and III SMA patients showed a significant improvement in muscle strength of legs at both 6 and 12 months after gabapentin treatment [ 114 ]. Meta-analysis of these two trials did not successfully demonstrate the beneficial effects of gabapentin in SMA [ 56 ].…”