Abstract:Histone acetylation plays an important role in regulation of transcription in eukaryotic cells by promoting a more relaxed chromatin structure necessary for transcriptional activation. Histone deacetylases (HDACs) remove acetyl groups and suppress gene expression. HDAC inhibitors (HDACIs) are a group of small molecules that promote gene transcription by chromatin remodeling and have been extensively studied as potential drugs for treating of spinal muscular atrophy. Various drugs in this class have been studie… Show more
“…Multiple approaches have been explored as potential methods to increase production of SMN protein from SMN2 , including increasing transcription [22, 24, 25, 26], modulating SMN2 exon 7 splicing [27–30], inducing translational read through of SMN Δ7 transcript [31], and increasing stability of SMN protein [32,33]. One of the most promising methods is the redirection of SMN2 splicing of exon 7 through antisense oligonucleotides (ASOs), short oligonucleotides designed to anneal to complementary sequences within a gene of interest [30, 34].…”
Section: Discovery Of Iss-n1 As Potential Therapeutic Targetmentioning
confidence: 99%
“…One promising approach which is the target of an ongoing clinical trial (NCT02386553) is to treat infants diagnosed with SMA-causing mutations but who have not yet experienced symptoms, thus preventing motor neuron degeneration before it can begin. Other approaches to increase expression of SMN, such as treatment with histone deacetylase (HDAC) inhibitors to increase transcription [25], have not shown sufficient efficacy for treatment of SMA by themselves, but may prove effective in combination with Spinraza™. SMA is not only a disease of motor neurons; low SMN levels can independently impact a number of somatic tissues [57, 58, 63–66] as well as the testis [13].…”
Section: Clinical Development Of Spinraza™ For the Treatment Of Smamentioning
Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza™ (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza™ showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza™ is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza™ underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.
“…Multiple approaches have been explored as potential methods to increase production of SMN protein from SMN2 , including increasing transcription [22, 24, 25, 26], modulating SMN2 exon 7 splicing [27–30], inducing translational read through of SMN Δ7 transcript [31], and increasing stability of SMN protein [32,33]. One of the most promising methods is the redirection of SMN2 splicing of exon 7 through antisense oligonucleotides (ASOs), short oligonucleotides designed to anneal to complementary sequences within a gene of interest [30, 34].…”
Section: Discovery Of Iss-n1 As Potential Therapeutic Targetmentioning
confidence: 99%
“…One promising approach which is the target of an ongoing clinical trial (NCT02386553) is to treat infants diagnosed with SMA-causing mutations but who have not yet experienced symptoms, thus preventing motor neuron degeneration before it can begin. Other approaches to increase expression of SMN, such as treatment with histone deacetylase (HDAC) inhibitors to increase transcription [25], have not shown sufficient efficacy for treatment of SMA by themselves, but may prove effective in combination with Spinraza™. SMA is not only a disease of motor neurons; low SMN levels can independently impact a number of somatic tissues [57, 58, 63–66] as well as the testis [13].…”
Section: Clinical Development Of Spinraza™ For the Treatment Of Smamentioning
Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza™ (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza™ showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza™ is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza™ underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.
“…SMA is a pediatric neuromuscular disorder characterized by the destruction of α ‐motor neurons in the anterior horn of the spinal cord and subsequent system‐wide muscle wasting . SMA is caused by insufficient levels of the protein SMN (survival motor neuron), a protein implicated in pre‐mRNA splicing, mRNA transport, and axonal growth …”
Histone deacetylases (HDACs) represent emerging therapeutic targets in the context of
neurodegeneration. Indeed, pharmacologic inhibition of HDACs activity in the nervous system has
shown beneficial effects in several preclinical models of neurological disorders. However, the
translation of such therapeutic approach to clinics has been only marginally successful, mainly due
to our still limited knowledge about HDACs physiological role particularly in neurons. Here, we
review the potential benefits along with the risks of targeting HDACs in light of what we currently
know about HDAC activity in the brain.
“…A number of HDAC inhibitors have been found to increase transcription of SMN2 , including suberoylanilidehydroxamic acid, trichostatin A, and US FDA approved drugs hydroxy-urea and valproic acid (Figure 3) [58]. However, clinical trials conducted with valproic acid and hydroxyurea did not show promising results [125–129].…”
Section: Transcriptional and Epigenetic Regulationmentioning
confidence: 99%
“…Select HDAC inhibitors that have been tested in mouse models of spinal muscular atrophy (SMA) and in the case of valproic acid in several clinical trials in SMA patients [58]. Rho kinase inhibitors [59,60] and the read-through compound TC007 [56] have also been tested in mouse models of SMA.…”
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 SMN2 exon 7 splicing, stabilize SMN/SMNΔ7 protein, manipulate SMN-regulated pathways and SMN1 gene delivery by viral vectors. This review focuses on the aspects of target discovery, validations and outcome measures for a promising therapy of SMA.
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