PMID- 32056234
OWN - NLM
STAT- MEDLINE
DCOM- 20200901
LR  - 20230701
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 153
IP  - 2
DP  - 2020 Apr
TI  - Combinatorial treatment for spinal muscular atrophy: An Editorial for 'Combined 
      treatment with the histone deacetylase inhibitor LBH589 and a splice-switch 
      antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal 
      Muscular Atrophy cells' on page 264.
PG  - 146-149
LID - 10.1111/jnc.14974 [doi]
AB  - Spinal muscular atrophy (SMA) is a severe autosomal recessive motor neuron 
      disease caused by the loss of SMN1, which encodes a protein essential for motor 
      neuron survival. SMA patients have one or more copies of an alternate SMN gene, 
      SMN2, which is nearly identical to SMN1. SMN2 differs at a single nucleotide from 
      SMN1 which results in the skipping of exon 7 in the mRNA and produces an unstable 
      protein (SMNDelta7). Therapeutic approaches that have been undertaken include (1) 
      replacement of SMN1 by gene delivery mediated by adeno-associated virus serotype 
      9 (AAV9) (Zolgensma), (2) correction of the aberrant SMN2 splicing using an 
      antisense oligonucleotide (ASO) or small molecule (nusinersin, risdiplam), and 
      (3) increased expression of SMN2 mediated by histone deacetylase (HDAC) 
      inhibitors. Two of these three approaches have given rise to successful 
      treatments for SMA, but they are very expensive, and their long-term safety is 
      not well known. In addition, the ability of ASOs and viral vectors to reach their 
      targets in the CNS with peripheral administration is limited. Small molecules may 
      cross the brain-blood barrier when orally delivered and can be discontinued if 
      needed to mitigate adverse effects. This Editorial highlights this study by 
      Pagliarni et al. in which they used combined treatment of cell models of SMA with 
      an ASO and an orally delivered HDAC inhibitor (panobinostat) to overcome the 
      limitations of a single-therapeutic approach. Panobinostat enhanced the 
      expression of SMN2, increasing the amount of SMN2 mRNA available for splicing 
      correction mediated by the ASO. In addition, panobinostat increased exon 7 
      retention in the SMN2 mRNA. This combinatorial treatment might allow lower or 
      less frequent ASO doses, reducing the need for repeated intrathecal 
      administration. The combined effects of panobinostat and nusinersen can now be 
      tested in SMA animal models to determine whether this approach will be 
      translatable to patients.
CI  - (c) 2020 International Society for Neurochemistry.
FAU - Poletti, Angelo
AU  - Poletti A
AUID- ORCID: 0000-0002-8883-0468
AD  - Dipartimento di Scienze Farmacologiche e Biomolecolari, Centre of Excellence on 
      Neurodegenerative Diseases, Universita degli Studi di Milano, Milano, Italy.
FAU - Fischbeck, Kenneth H
AU  - Fischbeck KH
AUID- ORCID: 0000-0002-8316-6895
AD  - Neurogenetics Branch, National Institute for Neurological Disorders and Stroke, 
      National Institutes of Health, Bethesda, MD, USA.
LA  - eng
GR  - Z01 NS003038/ImNIH/Intramural NIH HHS/United States
PT  - Comment
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200214
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (SMN2 protein, human)
RN  - 0 (Survival of Motor Neuron 2 Protein)
RN  - 9647FM7Y3Z (Panobinostat)
SB  - IM
CON - J Neurochem. 2020 Apr;153(2):264-275. PMID: 31811660
MH  - Animals
MH  - *Histone Deacetylase Inhibitors
MH  - Humans
MH  - *Muscular Atrophy, Spinal
MH  - Oligonucleotides, Antisense
MH  - Panobinostat
MH  - RNA Splicing
MH  - Survival of Motor Neuron 2 Protein
PMC - PMC10284344
MID - NIHMS1862642
COIS- CONFLICT OF INTEREST Angelo Poletti is an Editor for Journal of Neurochemistry.
EDAT- 2020/02/15 06:00
MHDA- 2020/09/02 06:00
PMCR- 2023/06/21
CRDT- 2020/02/15 06:00
PHST- 2020/01/13 00:00 [received]
PHST- 2020/01/23 00:00 [revised]
PHST- 2020/01/23 00:00 [accepted]
PHST- 2020/02/15 06:00 [pubmed]
PHST- 2020/09/02 06:00 [medline]
PHST- 2020/02/15 06:00 [entrez]
PHST- 2023/06/21 00:00 [pmc-release]
AID - 10.1111/jnc.14974 [doi]
PST - ppublish
SO  - J Neurochem. 2020 Apr;153(2):146-149. doi: 10.1111/jnc.14974. Epub 2020 Feb 14.