Spinal Muscular Atrophy: Therapeutic Strategies

Abstract

Spinal muscular atrophy is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to the reduction of SMN protein. The loss of alpha motor neurons in the ventral horn of the spinal cord results in progressive paralysis and premature death. There is no current treatment other than symptomatic and supportive care, although over the past decade, there has been an outstanding advancement in understanding the genetics and molecular mechanisms underlying the physiopathology of SMA. The most promising approach, from current trials, is the use of antisense oligonucleotide (ASOs) to redirect SMN2 translation and increase exon 7 inclusion in the majority of the RNA transcript, to increase the production of fully functional SMN protein. Recently, ISIS Pharmaceuticals Inc. (2855 Gazelle Court, Carlsbad CA 92010) reported an interim analysis from a multiple dose study in children with SMA between 2 and 14 years of age, using ASO therapy. The results indicated good tolerability at all dose levels, increases in muscle function in children treated with multiple doses of ISIS-SMNRx, and increase in SMN protein levels in cerebrospinal fluid (CSF) from both single and multiple dose studies. Studies in infants are ongoing in a few centers; soon other institutions may begin enrollment. Infants are fragile and their disease process may differ from the older SMA population. It is not known whether effective drug would best be given to SMA infants or older children. Other promising therapies are still in preclinical phases or early clinical phases. Gene therapy appears to be efficient in improving survival in a severe mouse model of SMA, though a better definition of the route of administration and of the safety profile of the viral vectors is needed before clinical administration is possible.

Review of Spinal Muscular Atrophy (SMA) for Prenatal and Pediatric Genetic Counselors

“…The aim of small molecules, which include histone deacetylase inhibitors such as aclarubicine (Andreassi et al 2001), sodium butyrate (Chang et al 2001), and valproic acid (Brichta et al 2003), is to increase the level of full-length proteins as made by the SMN2 gene. Pfizer (234 East 42nd Street, New York, NY 10017) is conducting phase I studies researching the ability of quinazolines to prohibit the breakdown of SMN2 RNA (Castro and Iannaccone 2014;Zanetta et al 2014a). However, most small molecule therapies have not proven to show consistent benefits in clinical trials (Kissel et al 2011;Swoboda et al 2009Swoboda et al , 2010Tsai 2012).…”

“…ISIS Pharmaceuticals Inc. (2855 Gazelle Court, Carlsbad CA 92010) is in the process of testing an ASO therapy (ISISSMNRx) that allows the nucleotides to bind to the mRNA sequence in the SMN2 gene. Then exon 7 of the SMN2 gene is able to be included in the sequencing instead of being repressed; thus, a full length and more functional SMN protein is created (Castro and Iannaccone 2014;Zanetta et al 2014a, b). In mice and nonhuman primates, the use of ISIS-SMNRx, a 2′-O-Methoxyethylmodified antisense drug, has shown the ability to increase the production of fully functional SMN protein (Rigo et al 2014).…”

“…In mice and nonhuman primates, the use of ISIS-SMNRx, a 2′-O-Methoxyethylmodified antisense drug, has shown the ability to increase the production of fully functional SMN protein (Rigo et al 2014). In the ISIS clinical trial phase I study, patients with types II and III SMAwere injected with an ASO into their intrathecal space, thus allowing for a bypass of the blood brain barrier and ensuring the drug can have an effect in the central nervous system (Castro and Iannaccone 2014). A phase II study is currently underway designed to examine the safety, tolerability and pharmacokinetics of multiple dose administration (Zanetta et al 2014a).…”

“…In 2014, a phase I clinical trial began at Nationwide Children's Hospital in Ohio. The study is investigating the ability of an adenovirus vector, AAV9, to cross the blood brain barrier and replace the missing SMN1 gene in patients with SMA (Castro and Iannaccone 2014;Zanetta et al 2014b). Viral gene therapy has shown an advantage of having a long survival time in preclinical studies with the need for only one delivery (Braun 2013).…”

“…The goal was to determine if the medication, a cholesterol-like molecule, could also aid the survival of motor neurons in human subjects. At this time, no results of the phase II study are available for review (Castro and Iannaccone 2014;Zanetta et al 2014a).…”