Abstract
Spinal muscular atrophy (SMA) is a genetic disorder with severity ranging from premature death in infants to restricted motor function in adult life. Despite the genetic cause of this disease being known for over twenty years, only recently has a therapy been approved to treat the most severe form of this disease. Here we discuss the genetic basis of SMA and the subsequent studies that led to the utilization of splice switching oligonucleotides to enhance production of SMN protein, which is absent in patients, through a mechanism of exon inclusion into the mature mRNA. Whilst approval of oligonucleotide-based therapies for SMA should be celebrated, we also discuss some of the limitations of this approach and alternate genetic strategies that are currently underway in clinical trials.
Highlights
Spinal muscular atrophy (SMA) is an autosomal recessive disorder that occurs in 1:6000–1:10,000 newborns [1] and is the leading genetic cause of infant mortality [2]
We have recently demonstrated the potential for cell-penetrating peptides (CPPs)-phosphorodiamidate morpholino (PMO) treatment of SMA in a study utilising low-dose intravenous administration in the severe SMA mouse model [24]
Clinical trial data does show an improvement for many patients there are still non-responders and improvement in clinical outcomes is varied
Summary
Spinal muscular atrophy (SMA) is an autosomal recessive disorder that occurs in 1:6000–1:10,000 newborns [1] and is the leading genetic cause of infant mortality [2]. The major pathological component of the disease is the selective loss of lower alpha motor neurons in the ventral horn of the spinal cord, resulting in progressive muscle denervation [3], skeletal muscle atrophy and eventually, paralysis and death [4]. SMN protein is ubiquitously expressed, motor neurons in the anterior horn of the spinal cord are most severely affected by SMN depletion [7] and restoration of muscle SMN protein alone is not enough for phenotypic improvement [8]. Recent Food and Drug Administration (FDA) approval has been granted for a splice-switching antisense drug for SMA and in this review we outline the preclinical and clinical studies that led to this approval as well as discuss potential strategies to overcome constraints in current treatment possibilities
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