Spinal muscular atrophy: Difference between revisions

[[Newborn screening|Routine newborn screening]] for SMA is becoming increasingly commonplace in developed countries, given the availability of causative treatments that are most effective at the asymptomatic stage of the disease.<ref>{{cite journal|vauthors=Serra-Juhe C, Tizzano EF|date=December 2019|title=Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors|journal=European Journal of Human Genetics|volume=27|issue=12|pages=1774–1782|doi=10.1038/s41431-019-0415-4|pmc=6871529|pmid=31053787}}</ref><ref>{{cite journal|display-authors=6|vauthors=Glascock J, Sampson J, Haidet-Phillips A, Connolly A, Darras B, Day J, Finkel R, Howell RR, Klinger K, Kuntz N, Prior T, Shieh PB, Crawford TO, Kerr D, Jarecki J|date=2018-05-29|title=Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening|journal=Journal of Neuromuscular Diseases|volume=5|issue=2|pages=145–158|doi=10.3233/JND-180304|pmc=6004919|pmid=29614695}}</ref><ref>{{cite journal|vauthors=Dangouloff T, Burghes A, Tizzano EF, Servais L|date=January 2020|title=244th ENMC international workshop: Newborn screening in spinal muscular atrophy May 10-12, 2019, Hoofdorp, The Netherlands|journal=Neuromuscular Disorders|volume=30|issue=1|pages=93–103|doi=10.1016/j.nmd.2019.11.002|pmid=31882184|doi-access=free|hdl=2268/242772 |url=https://orbi.uliege.be/bitstream/2268/242772/1/Dangouloff%20ENMC.pdf}}</ref> In 2018, newborn screening for SMA was added to the US list of recommended newborn screening tests<ref>{{Cite web|last=Lopes|first=Jose Marques|name-list-style=vanc|date=2018-07-16|title=SMA Added to List of Recommended Screenings for Disease Given to...|url=https://smanewstoday.com/2018/07/16/sma-added-to-us-list-of-diseases-recommended-for-newborn-screening/|access-date=2020-05-04|website=SMA News Today|language=en-US}}</ref><ref>{{Cite web|last=Stephenson|first=Kristin|name-list-style=vanc|date=2018-07-05|title=SMA Added to National List of Disorders to Screen for at Birth|url=https://strongly.mda.org/sma-added-national-list-disorders-to-screen-for-at-birth/|access-date=2020-05-04|website=Muscular Dystrophy Association|language=en-US}}</ref><ref>{{Cite web|date=2017-07-03|title=Recommended Uniform Screening Panel|url=https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp/index.html|access-date=2020-05-04|website=Official web site of the U.S. Health Resources & Services Administration|language=en}}</ref> and as of April 2020 it has been adopted in 39 US states.<ref>{{Cite web|last=McCall|first=Sarah|name-list-style=vanc|title=Newborn Screening for Spinal Muscular Atrophy|url=https://www.curesma.org/newborn-screening-for-sma/|access-date=2020-05-04|website=Cure SMA|language=en-US}}</ref><ref>{{cite journal|display-authors=6|vauthors=Kraszewski JN, Kay DM, Stevens CF, Koval C, Haser B, Ortiz V, Albertorio A, Cohen LL, Jain R, Andrew SP, Young SD, LaMarca NM, De Vivo DC, Caggana M, Chung WK|date=June 2018|title=Pilot study of population-based newborn screening for spinal muscular atrophy in New York state|journal=Genetics in Medicine|volume=20|issue=6|pages=608–613|doi=10.1038/gim.2017.152|pmid=29758563|doi-access=free}}</ref> As of February 2023, SMA screening has been incorporated in national newborn screening programmes in around 15 countries and pilot projects are under way in further countries.<ref>{{Cite web |title=SMA Newborn Screening Alliance – SMA: Test at birth, save a life |url=https://www.sma-screening-alliance.org/ |access-date=2023-02-05 |language=en-GB}}</ref>

[[Risdiplam]] (marketed as Evrysdi) is a medication taken [[Oral administration|by mouth]] in liquid form.<ref name="FDA risdiplam" /><ref name="Evrysdi label">{{cite web |url=https://www.gene.com/download/pdf/evrysdi_prescribing.pdf | publisher=Genentech | title=Evrysdi (risdiplam) for oral solution | access-date=8 August 2020}}</ref> It is a [[pyridazine]] derivative that works by increasing the amount of functional [[survivor motor neuron]] protein produced by the [[SMN2|''SMN2'' gene]] through [[alternative splicing|modifying its splicing pattern]].<ref>{{cite web| url=https://smanewstoday.com/rg7916-rg7800-roche-ptc-smaf | title=RG7916 | author=Maria Joao Almeida | publisher=BioNews Services | date=2016-09-08 | access-date=2017-10-08 }}</ref><ref>{{cite journal | vauthors = Zhao X, Feng Z, Ling KK, Mollin A, Sheedy J, Yeh S, Petruska J, Narasimhan J, Dakka A, Welch EM, Karp G, Chen KS, Metzger F, Ratni H, Lotti F, Tisdale S, Naryshkin NA, Pellizzoni L, Paushkin S, Ko CP, Weetall M | display-authors = 6 | title = Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy | journal = Human Molecular Genetics | volume = 25 | issue = 10 | pages = 1885–1899 | date = May 2016 | pmid = 26931466 | pmc = 5062580 | doi = 10.1093/hmg/ddw062 }}</ref> Risdiplam aims to increase the amount of SMN protein so that there is enough protein to sustain the peripheral nervous system tissues which are usually the most damaged by SMA.<ref>{{cite journal |last1=Zhu |first1=Xiaoying |title=Comparison of Nusinersen and Evrysdi in the Treatment of Spinal Muscular Atrophy |journal=E3S Web Conferences |date=15 June 2021 |volume=271 |issue=2021 |series=2nd International Academic Conference on Energy Conservation, Environmental Protection and Energy Science (ICEPE 2021) |page=03035 |doi=10.1051/e3sconf/202127103035 |bibcode=2021E3SWC.27103035Z |s2cid=236740376 |url=https://www.e3s-conferences.org/articles/e3sconf/abs/2021/47/e3sconf_icepe2021_03035/e3sconf_icepe2021_03035.html |access-date=11 December 2023}}</ref> Risdiplam was first approved for medical use in the United States in August 2020<ref name="FDA risdiplam">{{cite press release | title=FDA Approves Oral Treatment for Spinal Muscular Atrophy | website=U.S. [[Food and Drug Administration]] (FDA) | date=7 August 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy | access-date=7 August 2020}}</ref> and has since been approved in over 30 countries.{{cn|date=November 2023}}

Historically, this research direction investigated also other molecules. RG3039, also known as Quinazoline495, was a proprietary [[quinazoline]] derivative developed by [[Repligen]] and licensed to [[Pfizer]] in March 2014 which was discontinued shortly after, having only completed phase I trials. PTK-SMA1 was a proprietary small-molecule splicing modulator of the [[tetracycline]]s group developed by Paratek Pharmaceuticals and about to enter clinical development in 2013 which however never happened due to Paratek downsizing at that time. RG7800, developed by Hoffmann-La Roche, was a molecule akin to risdiplam that has undergone phase I testing but was discontinued due to animal toxicity.<ref name="Kletzl Marquet Günther Tang 2019 pp. 21–29">{{cite journal | last1=Kletzl | first1=Heidemarie | last2=Marquet | first2=Anne | last3=Günther | first3=Andreas | last4=Tang | first4=Wakana | last5=Heuberger | first5=Jules | last6=Groeneveld | first6=Geert Jan | last7=Birkhoff | first7=Willem | last8=Mercuri | first8=Eugenio | last9=Lochmüller | first9=Hanns | last10=Wood | first10=Claire | last11=Fischer | first11=Dirk | last12=Gerlach | first12=Irene | last13=Heinig | first13=Katja | last14=Bugawan | first14=Teodorica | last15=Dziadek | first15=Sebastian | last16=Kinch | first16=Russell | last17=Czech | first17=Christian | last18=Khwaja | first18=Omar | title=The oral splicing modifier RG7800 increases full length survival of motor neuron 2 mRNA and survival of motor neuron protein: Results from trials in healthy adults and patients with spinal muscular atrophy | journal=Neuromuscular Disorders | publisher=Elsevier BV | volume=29 | issue=1 | year=2019 | issn=0960-8966 | doi=10.1016/j.nmd.2018.10.001 | pages=21–29| pmid=30553700 | s2cid=54315649 }}</ref> Early leads also included [[sodium orthovanadate]]<ref>{{cite journal | vauthors = Zhang ML, Lorson CL, Androphy EJ, Zhou J | title = An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: potential therapy of SMA | journal = Gene Therapy | volume = 8 | issue = 20 | pages = 1532–8 | date = October 2001 | pmid = 11704813 | doi = 10.1038/sj.gt.3301550 | doi-access = | s2cid = 29685631 }}</ref> and [[aclarubicin]].<ref>{{cite journal | vauthors = Andreassi C, Jarecki J, Zhou J, Coovert DD, Monani UR, Chen X, Whitney M, Pollok B, Zhang M, Androphy E, Burghes AH | title = Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients | journal = Human Molecular Genetics | volume = 10 | issue = 24 | pages = 2841–9 | date = November 2001 | pmid = 11734549 | doi = 10.1093/hmg/10.24.2841 | doi-access = free }}</ref>