iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: http://pubmed.ncbi.nlm.nih.gov/29985170/
Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Aug 1;128(8):3219-3227.
doi: 10.1172/JCI121658. Epub 2018 Jul 9.

Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain

Charlotte J Sumner  1   2 , Thomas O Crawford  1   3
Affiliations
Review

Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain

Charlotte J Sumner et al. J Clin Invest. .

Abstract

The motor neuron disease spinal muscular atrophy (SMA) is caused by recessive, loss-of-function mutations of the survival motor neuron 1 gene (SMN1). Alone, such mutations are embryonically lethal, but SMA patients retain a paralog gene, SMN2, that undergoes alternative pre-mRNA splicing, producing low levels of SMN protein. By mechanisms that are not well understood, reduced expression of the ubiquitously expressed SMN protein causes an early-onset motor neuron disease that often results in infantile or childhood mortality. Recently, striking clinical improvements have resulted from two novel treatment strategies to increase SMN protein by (a) modulating the splicing of existing SMN2 pre-mRNAs using antisense oligonucleotides, and (b) transducing motor neurons with self-complementary adeno-associated virus 9 (scAAV9) expressing exogenous SMN1 cDNA. We review the recently published clinical trial results and discuss the differing administration, tissue targeting, and potential toxicities of these two therapies. We also focus on the challenges that remain, emphasizing the many clinical and biologic questions that remain open. Answers to these questions will enable further optimization of these remarkable SMA treatments as well as provide insights that may well be useful in application of these therapeutic platforms to other diseases.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: CJS has been a consultant to Avexis, Ionis Pharmaceuticals, Biogen, SMA Foundation, PTC Therapeutics, and Roche. CJS received a research grant from Ionis Pharmaceuticals in 2016 ($75,000).CJS is a coholder of 2 pending patent applications (BIOL0274USA and BIOL0293WO) with Ionis Pharmaceuticals on antisense oligonucleotides targeting SMN-AS1. TOC has been a consultant to Ionis Pharmaceuticals, Biogen, and Avexis. He is/has been a site principal investigator for the EMBRACE and NURTURE Biogen clinical trials and the current STRIVE and STRONG Avexis trials.

Figures

Figure 1
Figure 1. The SMN1 and SMN2 genes that cause SMA can each be targeted by different therapeutic strategies.
(A) SMN1 and SMN2 gene expression in a healthy individual. (B) Schematic of SMA genetics. (C) Therapeutic mechanism of scAAV9-SMN1 cDNA, the splice-switching ASO, and the small molecules risdiplam (RG7916) and branaplam (LMI070) currently in clinical trials (see Table 1).
Figure 2
Figure 2. The clinical course of SMA and alterations with treatment.
(A) A schematic depiction of the usual clinical course of SMA types I, II, and III. The general trend of functional loss is greatest at the outset of disease and diminishes thereafter. In some cases, the earliest course manifests as departure from the path of normal development, with some transient gains before loss of ability is seen. (B) Green lines indicate variable hypothetical therapeutic responses, which depend on timing of drug administration (green circles) and the magnitude of preexisting motor neuron degeneration.
Figure 3
Figure 3. Schematic of cell types directly interacting with motor neurons.
The motor unit is composed of multiple cell types that may be affected directly or secondarily by SMN deficiency.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Werdnig G. Zwei frühinfantile hereditäre fälle von progressive muskelatrophie unter dem bilde der dystrophie, aber auf neurotischer grundlage. Arch fur Psychiatr Nervenkrankh. 1891;22:437–481. doi: 10.1007/BF01776636. - DOI
    1. Lefebvre S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–165. doi: 10.1016/0092-8674(95)90460-3. - DOI - PubMed
    1. Lefebvre S, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997;16(3):265–269. doi: 10.1038/ng0797-265. - DOI - PubMed
    1. Parsons DW, McAndrew PE, Iannaccone ST, Mendell JR, Burghes AH, Prior TW. Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number. Am J Hum Genet. 1998;63(6):1712–1723. doi: 10.1086/302160. - DOI - PMC - PubMed
    1. Finkel RS, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723–1732. doi: 10.1056/NEJMoa1702752. - DOI - PubMed

Publication types

MeSH terms

Substances