SMA follows autosomal recessive inheritance. All forms of 5q-SMA (type 1–4) have an incidence of 1/6000–10,000 world-wide. However, after the identification of the underlying gene defect, it became apparent that both diseases are caused by homozygous deletion of the Survival Motor Neuron 1 ( SMN1) gene on human chromosome 5q13.2. A milder form of proximal spinal muscular atrophy also exists that originally has been considered as a distinct neurological disease. The severe form of proximal spinal muscular atrophy, also called Werdnig-Hoffmann disease, is the most common monogenetic lethal pediatric neuromuscular disorder. The second part addresses opportunities and challenges associated with further development of these approaches for treatment of other neurodegenerative disorders and muscular dystrophies.ĭisease presentation and classification of spinal muscular atrophy (SMA) Our review summarizes the development of antisense-oligonucleotide (ASO) and gene therapy for SMA, based on the literature search via and released data from. This offers further technical opportunities for interference with other neurodegenerative mechanisms. Oligonucleotide therapies do not exclusively offer the chance to increase expression of proteins such as SMN, but also to repress expression of mutant proteins with pathological function in other neurodegenerative disorders. Experience with such therapies is rapidly progressing, and this also has impact on therapy development for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Thus, oligonucleotide-based therapies as well as gene therapies are currently tested in these disorders. Restoration of protein expression is also a central goal for therapy development in Duchenne-and Becker-type muscular dystrophies. Thus, approaches to suppress alternative splicing of this exon and an AAV9-based gene therapy for enhanced expression of the SMN protein in motoneurons have led to success in treating degeneration of motoneurons in this disease. SMN2 differs from SMN1 by a single C to T transition in exon 7, leading to increased skipping of exon 7. The specific architecture on human chromosome 5 with a second SMN gene ( SMN2) is responsible for the cellular production of low levels of SMN protein that are not sufficient to maintain structure and function of motoneurons. Thus, therapeutic approaches so far have focused on restoration of SMN expression. It is caused by homozygous loss of function (LOF) mutations of the Survival Motor Neuron 1 (SMN1) gene on human chromosome 5(5q13.2). Spinal muscular atrophy (SMA) is the most common form of a lethal pediatric neuromuscular disorder with autosomal recessive inheritance.
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