Advances in therapeutic development for spinal muscular atrophy.
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ABSTRACT:
SUBMITTER: Howell MD
PROVIDER: S-EPMC4356243 | biostudies-literature | 2014 Jun
REPOSITORIES: biostudies-literature
Publications
Advances in therapeutic development for spinal muscular atrophy.
Howell Matthew D MD Singh Natalia N NN Singh Ravindra N RN
Future medicinal chemistry 20140601 9
Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The disease originates from low levels of SMN protein due to deletion and/or mutations of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1. While SMN1 and SMN2 are nearly identical, SMN2 predominantly generates a truncated protein (SMNΔ7) due to skipping of exon 7, the last coding exon. Several avenues for SMA therapy are being explored, including means to enhance SMN2 transcription, correct S ...[more]
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Project description:PURPOSE OF REVIEW:Spinal muscular atrophy (SMA) is a genetic disorder of motor neurons in the anterior horns of the spinal cord and brainstem that results in muscle atrophy and weakness. SMA is an autosomal recessive disease linked to deletions of the SMN1 gene on chromosome 5q. Humans have a duplicate gene (SMN2) whose product can mitigate disease severity, leading to the variability in severity and age of onset of disease, and is therefore a target for drug development. RECENT FINDINGS:Advances in preclinical and clinical trials have paved the way for novel therapeutic options for SMA patients, including many currently in clinical trials. In 2016, the first treatment for SMA has been approved in the USA, an antisense oligonucleotide that increases full-length protein product derived from SMN2. The approval of a first treatment for SMA and the rapid advances in clinical trials provide the prospect for multiple approaches to disease modification. There are several other promising therapeutics in different stages of development, based on approaches such as neuroprotection, or gene therapy.
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Project description:Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families. Greater knowledge of the molecular basis of SMA pathogenesis has fuelled the development of potential therapeutic approaches, which are illustrated here. Nusinersen, a modified antisense oligonucleotide that modulates the splicing of the SMN2 mRNA transcript, is the first approved drug for all types of SMA. Moreover, the first gene therapy clinical trial using adeno-associated virus (AAV) vectors encoding SMN reported positive results in survival and motor milestones achievement. In addition, other strategies are in the pipeline, including modulation of SMN2 transcripts, neuroprotection, and targeting an increasing number of other peripheral targets, including the skeletal muscle. Based on this premise, it is reasonable to expect that therapeutic approaches aimed at treating SMA will soon be changed, and improved, in a meaningful way. We discuss the challenges with regard to the development of novel treatments for patients with SMA, and depict the current and future scenarios as the field enters into a new era of promising effective treatments.
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Project description:Spinal muscular atrophy (SMA) is an inherited childhood neurodegenerative disorder caused by ubiquitous deficiency of the survival motor neuron (SMN) protein - the hallmarks of which are the selective loss of motor neurons and skeletal muscle atrophy. Here, we highlight recent progress in the understanding of SMA pathology and in the development of therapeutic approaches for its treatment.Phenotypic characterization of mouse models of the disease, combined with analysis of SMN restoration or depletion in a spatially and temporally controlled manner, has yielded key insights into the normal requirement of SMN and SMA pathophysiology. Increasing evidence indicates a higher demand for SMN during neuromuscular development and extends the pathogenic effects of SMN deficiency beyond motor neurons to include additional cells both within and outside the nervous system. These findings have been paralleled by preclinical development of powerful approaches for increasing SMN expression through gene therapy or splicing modulation that are now in human trials.Along with the availability of SMN-upregulating drugs, identification of the specific cell types in which SMN deficiency induces the disease and delineation of the window of opportunity for effective treatment are key advances in the ongoing path to SMA therapy.
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Project description:Spinal muscular atrophy (SMA), a potentially devastating disease marked by progressive weakness and muscle atrophy resulting from the dysfunction and loss of motor neurons of the spinal cord, has emerged in recent years as an attractive target for therapeutic intervention. Caused by a homozygous mutation to the Survival of Motor Neurons 1 (SMN1) gene on chromosome 5q, the severity of the clinical phenotype in SMA is modulated by the function of a related protein, Survival of Motor Neurons 2 (SMN2). SMN2 predominantly produces an unstable SMN transcript lacking exon 7; only about 10% of the transcription product produces a full-length, functional SMN protein. Several therapeutic strategies have targeted this gene with the goal of producing increased full-length SMN transcript, thereby modifying the underlying mechanism. Drugs that have increased SMN2 function, in vitro, are now explored for potential therapeutic benefit in this disease. Alternative approaches, including neuroprotective, muscle anabolic, gene and cell replacement strategies, also hold promise. The recent advances in preclinical research and the development of a wider range of animal models for SMA continue to provide cautious optimism that effective treatments for SMA will eventually emerge.
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Project description:The motor neuron degenerative disease spinal muscular atrophy (SMA) remains one of the most frequently inherited causes of infant mortality. Afflicted patients loose the survival motor neuron 1 (SMN1) gene but retain one or more copies of SMN2, a homolog that is incorrectly spliced. Primary treatment strategies for SMA aim at boosting SMN protein levels, which are insufficient in patients. SMN is known to partner with a set of diverse proteins collectively known as GEMINs to form a macromolecular complex. The SMN-GEMINs complex is indispensible for chaperoning the assembly of small nuclear ribonucleoproteins (snRNPs), which are key for pre-mRNA splicing. Pharmaceutics that alleviate the neuromuscular phenotype by restoring the fundamental function of SMN without augmenting its levels are also crucial in the development of an effective treatment. Their use as an adjunct therapy is predicted to enhance benefit to patients. Inspired by the surprising discovery revealing a premier role for GEMINs in snRNP biogenesis together with in vivo studies documenting their requirement for the correct function of the motor system, this review speculates on whether GEMINs constitute valid targets for SMA therapeutic development.
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Project description:Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMN?7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMN?7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA.
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Project description:Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1 A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery.
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