Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy

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 studied with regard to their efficacy in increasing the expression of survival of motor neuron (SMN) protein. In this review, we discuss the current literature on this topic and summarize the findings of the main studies in this field.

ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy

“…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].…”

“…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].…”

The promise and perils of HDAC inhibitors in neurodegeneration

“…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 …”

Advances in Therapeutic Development for Spinal Muscular Atrophy

“…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].…”

“…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.…”