Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Treatment of Adult Spinal Muscular Atrophy: Overview and Recent Developments

Author(s): Svenja Brakemeier, Benjamin Stolte, Christoph Kleinschnitz and Tim Hagenacker*

Volume 28, Issue 11, 2022

Published on: 22 April, 2022

Page: [892 - 898] Pages: 7

DOI: 10.2174/1381612828666220329115433

Price: $65

conference banner
Abstract

Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disease leading to progressive and, in many cases, severe muscle weakness and atrophy in the natural disease course. An increasing number of gene-based treatment options have become available in recent years. Growing knowledge regarding the underlying genetic mechanisms makes the disease well amenable to them. Over the past few years, data on new treatments, their mechanisms of action and therapeutic outcomes have been published, reflecting the current dynamics in this field. With the approval of the antisense oligonucleotide nusinersen, the vector-based therapy with onasemnogene abeparvovec and the small molecule splicing modifier risdiplam, three gene therapeutic drugs are available for the treatment of SMA showing improvement in motor function. But in the pivotal studies, several relevant parameters have not been addressed. There is a data gap for the treatment outcome of adult individuals with SMA as well as for several other relevant outcome parameters, like bulbary or ventilatory function. With increasing treatment options, additional individual therapies have become necessary. Studies on combination therapies or switch of therapy, e.g., the sequential administration of onasemnogen abeparvovec and nusinersen, are necessary. An overview of current developments in the field of therapeutic options for adult SMA is presented. Important characteristics of each therapeutic options are discussed so that the reader can comprehend underlying pathophysiological mechanisms as well as advantages and disadvantages of each therapy. The focus is on gene-based treatment options, but options beyond this are also addressed.

Keywords: Spinal muscular atrophy, gene-based therapy, therapeutic options, SMA, pathophysiology of SMA, genotype-phenotype correlation.

« Previous Next »
[1]
Verhaart IEC, Robertson A, Wilson IJ, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis 2017; 12(1): 124.
[http://dx.doi.org/10.1186/s13023-017-0671-8] [PMID: 28676062]
[2]
Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995; 80(1): 155-65.
[http://dx.doi.org/10.1016/0092-8674(95)90460-3] [PMID: 7813012]
[3]
Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin 2015; 33(4): 831-46.
[http://dx.doi.org/10.1016/j.ncl.2015.07.004] [PMID: 26515624]
[4]
Lunn MR, Wang CH. Spinal muscular atrophy. Lancet 2008; 371(9630): 2120-33.
[http://dx.doi.org/10.1016/S0140-6736(08)60921-6] [PMID: 18572081]
[5]
Russman BS. Spinal muscular atrophy: Clinical classification and disease heterogeneity. J Child Neurol 2007; 22(8): 946-51.
[http://dx.doi.org/10.1177/0883073807305673] [PMID: 17761648]
[6]
Wadman RI, Wijngaarde CA, Stam M, et al. Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c-4. Eur J Neurol 2018; 25(3): 512-8.
[http://dx.doi.org/10.1111/ene.13534] [PMID: 29194869]
[7]
Souza PVS, Pinto WBVR, Ricarte A, et al. Clinical and radiological profile of patients with spinal muscular atrophy type 4. Eur J Neurol 2021; 28(2): 609-19.
[http://dx.doi.org/10.1111/ene.14587] [PMID: 33090613]
[8]
Farrar MA, Kiernan MC. The genetics of spinal muscular atrophy: Progress and challenges. Neurotherapeutics 2015; 12(2): 290-302.
[http://dx.doi.org/10.1007/s13311-014-0314-x] [PMID: 25413156]
[9]
Fallini C, Bassell GJ, Rossoll W. Spinal muscular atrophy: The role of SMN in axonal mRNA regulation. Brain Res 2012; 1462: 81-92.
[http://dx.doi.org/10.1016/j.brainres.2012.01.044] [PMID: 22330725]
[10]
Kolb SJ, Battle DJ, Dreyfuss G. Molecular functions of the SMN complex. J Child Neurol 2007; 22(8): 990-4.
[http://dx.doi.org/10.1177/0883073807305666] [PMID: 17761654]
[11]
Monani UR, Lorson CL, Parsons DW, et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999; 8(7): 1177-83.
[http://dx.doi.org/10.1093/hmg/8.7.1177] [PMID: 10369862]
[12]
Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 1999; 96(11): 6307-11.
[http://dx.doi.org/10.1073/pnas.96.11.6307] [PMID: 10339583]
[13]
Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 1997; 16(3): 265-9.
[http://dx.doi.org/10.1038/ng0797-265] [PMID: 9207792]
[14]
Feldkötter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: Fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet 2002; 70(2): 358-68.
[http://dx.doi.org/10.1086/338627] [PMID: 11791208]
[15]
Wirth B. Spinal muscular atrophy: In the challenge lies a solution. Trends Neurosci 2021; 44(4): 306-22.
[http://dx.doi.org/10.1016/j.tins.2020.11.009] [PMID: 33423791]
[16]
Glanzman AM, Mazzone E, Main M, et al. The children’s hospital of Philadelphia infant test of neuromuscular disorders (CHOP INTEND): Test development and reliability The CHOP INTEND is a reliable measure of motor skills in patients with SMA-I and neuromuscular disorders presenting in infancy. Neuromuscul Disord 2010; 20(3): 155-61.
[http://dx.doi.org/10.1016/j.nmd.2009.11.014] [PMID: 20074952]
[17]
Pera MC, Coratti G, Forcina N, et al. Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC Neurol 2017; 17(1): 39.
[http://dx.doi.org/10.1186/s12883-017-0790-9] [PMID: 28231823]
[18]
McGraw S, Qian Y, Henne J, Jarecki J, Hobby K, Yeh WS. A qualitative study of perceptions of meaningful change in spinal muscular atrophy. BMC Neurol 2017; 17(1): 68.
[http://dx.doi.org/10.1186/s12883-017-0853-y] [PMID: 28376816]
[19]
King W, Kissel JT, Montes J, De Vivo DC, Finkel RS. Six-minute walk test demonstrates motor fatigue in spinal muscular atrophy. Neurology 2010; 75(12): 1121-2.
[http://dx.doi.org/10.1212/WNL.0b013e3181f00304] [PMID: 20855858]
[20]
Sardone V, Zhou H, Muntoni F, Ferlini A, Falzarano MS. Antisense oligonucleotide-based therapy for neuromuscular disease. Molecules 2017; 22(4): 563.
[http://dx.doi.org/10.3390/molecules22040563] [PMID: 28379182]
[21]
Passini MA, Bu J, Richards AM, et al. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med 2011; 3(72)72ra18
[http://dx.doi.org/10.1126/scitranslmed.3001777] [PMID: 21368223]
[22]
Hua Y, Sahashi K, Rigo F, et al. Peripheral SMN restoration is essential for long-term rescue of a severe SMA mouse model. Nature 2012; 478: 123-6.
[http://dx.doi.org/10.1038/nature10485] [PMID: 21979052]
[23]
Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study. Lancet 2016; 388(10063): 3017-26.
[http://dx.doi.org/10.1016/S0140-6736(16)31408-8] [PMID: 27939059]
[24]
Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017; 377(18): 1723-32.
[http://dx.doi.org/10.1056/NEJMoa1702752] [PMID: 29091570]
[25]
Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med 2018; 378(7): 625-35.
[http://dx.doi.org/10.1056/NEJMoa1710504] [PMID: 29443664]
[26]
De Vivo DC, Bertini E, Swoboda KJ, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord 2019; 29(11): 842-56.
[http://dx.doi.org/10.1016/j.nmd.2019.09.007] [PMID: 31704158]
[27]
SMA screening for newborns in Europe – bridging the gap. Roche Available from:. https://www.roche.com/research_and_development/what_we_are_working_on/neuroscience/spinal-muscular-atrophy/screening-for-newborns.htm accessed on 2021 November 7
[28]
Hagenacker T, Wurster CD, Günther R, et al. Nusinersen in adults with 5q spinal muscular atrophy: A non-interventional, multicentre, observational cohort study. Lancet Neurol 2020; 19(4): 317-25.
[http://dx.doi.org/10.1016/S1474-4422(20)30037-5] [PMID: 32199097]
[29]
Walter MC, Wenninger S, Thiele S, et al. Safety and treatment effects of nusinersen in longstanding adult 5q-SMA type 3 - a prospective observational study. J Neuromuscul Dis 2019; 6(4): 453-65.
[http://dx.doi.org/10.3233/JND-190416] [PMID: 31594243]
[30]
Stolte B, Totzeck A, Kizina K, et al. Feasibility and safety of intrathecal treatment with nusinersen in adult patients with spinal muscular atrophy. Ther Adv Neurol Disord 2018; 111756286418803246
[http://dx.doi.org/10.1177/1756286418803246] [PMID: 30305849]
[31]
Wurster CD, Winter B, Wollinsky K, et al. Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients. J Neurol 2019; 266(1): 183-94.
[http://dx.doi.org/10.1007/s00415-018-9124-0] [PMID: 30460449]
[32]
Flotats-Bastardas M, Hahn A, Schwartz O, et al. Multicenter experience with nusinersen application via an intrathecal port and catheter system in spinal muscular atrophy. Neuropediatrics 2020; 51(6): 401-6.
[http://dx.doi.org/10.1055/s-0040-1715481] [PMID: 33091940]
[33]
ClinicalTrials.gov Study of Nusinersen (BIIB058) in ParticipantsWith Spinal Muscular Atrophy (DEVOTE). Available from:. https://clinicaltrials.gov/ct2/show/NCT04089566 Accessed on 2021 November 8).
[34]
ClinicalTrials.gov.A Study of nusinersen among participants with spinal muscular atrophy who received onasemnogene abeparvovec (RESPOND). Available from:. https://clinicaltrials.gov/ct2/show/NCT04488133 (Accessed on 2021 November 8).
[35]
Biogen plans to initiate phase 3B study evaluating potential benefit of a higher dose of nusinersen in patients previously treated with evrysdi® (risdiplam). Available from:. https://investors.biogen.com/news-releases/news-release-details/biogen-plans-initiate-phase-3b-study-evaluating-potential (Accessed on 2021 November 8).
[36]
Product information zolgensma. European Agency Medicines (EMA). Available from:. https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensm (Accessed on 2021 November 8).
[37]
Foust KD, Wang X, McGovern VL, et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 2010; 28(3): 271-4.
[http://dx.doi.org/10.1038/nbt.1610] [PMID: 20190738]
[38]
Dominguez E, Marais T, Chatauret N, et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet 2011; 20(4): 681-93.
[http://dx.doi.org/10.1093/hmg/ddq514] [PMID: 21118896]
[39]
Boutin S, Monteilhet V, Veron P, et al. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: Implications for gene therapy using AAV vectors. Hum Gene Ther 2010; 21(6): 704-12.
[http://dx.doi.org/10.1089/hum.2009.182] [PMID: 20095819]
[40]
Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017; 377(18): 1713-22.
[http://dx.doi.org/10.1056/NEJMoa1706198] [PMID: 29091557]
[41]
Mendell JR, Al-Zaidy SA, Lehman KJ, et al. 2021.Five-year extension results of the phase 1 start trialof onasemnogene abeparvovec in spinal muscular atrophyJAMA Neurol Available from: https://jamanetwork.com/journals/jamaneurology/fullarticle/2780250
[42]
Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): An open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol 2021; 20(4): 284-93.
[http://dx.doi.org/10.1016/S1474-4422(21)00001-6] [PMID: 33743238]
[43]
Al-Zaidy SA, Kolb SJ, Lowes L, et al. AVXS-101 (onasemnogene abeparvovec) for SMA1: Comparative study with a prospective natural history cohort. J Neuromuscul Dis 2019; 6(3): 307-17.
[http://dx.doi.org/10.3233/JND-190403] [PMID: 31381526]
[44]
Saunders NR, Liddelow SA, Dziegielewska KM. Barrier mechanisms in the developing brain. Front Pharmacol 2012; 3: 46.
[http://dx.doi.org/10.3389/fphar.2012.00046] [PMID: 22479246]
[45]
NCT03381729. Study of intrathecal administration of onasemnogene abeparvovec-xioi for spinal muscular atrophy (STRONG). Available from:. https://clinicaltrials.gov/ct2/show/NCT03381729
[46]
Product Information Evrysdi. European Medicines Agency (EMA) Available from:. https://www.ema.europa.eu/en/medicines/human/EPAR/evrysdi (Accessed on 2021 June 4).
[47]
Naryshkin NA, Weetall M, Dakka A, et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 2014; 345(6197): 688-93.
[http://dx.doi.org/10.1126/science.1250127] [PMID: 25104390]
[48]
Poirier A, Weetall M, Heinig K, et al. Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs. Pharmacol Res Perspect 2018; 6(6)e00447
[http://dx.doi.org/10.1002/prp2.447] [PMID: 30519476]
[49]
Baranello G, Darras BT, Day JW, et al. risdiplam in type 1 spinal muscular atrophy. N Engl J Med 2021; 384(10): 915-23.
[http://dx.doi.org/10.1056/NEJMoa2009965] [PMID: 33626251]
[50]
Mercuri E, Baranello G, Kirschner J, et al. 2018 SUNFISH Part 1: Risdiplam (RG7916) treatment results in a sustained increase of SMN protein levels and improvement in motor function in patients with Type 2 or 3 SMA: Presented at the 23rd International Annual Congress of the World Muscle Society; 2018 Oct 2-6; Mendoza, Argentina. Available from:. https://medically.roche.com/content/dam/pdmahub/non-restricted/neurology/wms-2018/WMS_2018_ SUNFISH_risdiplam_poster_Mercuri.pdf (Accessed on 2021 June 10).
[51]
ClinicalTrials.gov. A study of risdiplam in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (Rainbowfish). Available from:. https://clinicaltrials.gov/ct2/show/NCT03779334 (Accessed on 2021 November 8).
[52]
Cheung AK, Hurley B, Kerrigan R, et al. Discovery of small molecule splicing modulators of survival motor neuron-2 (SMN2) for the treatment of spinal muscular atrophy (SMA). J Med Chem 2018; 61(24): 11021-36.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01291] [PMID: 30407821]
[53]
Novartis receives US Food and Drug Administration (FDA) Orphan Drug Designation for branaplam (LMI070) in Huntington’s disease (HD). Novartis. Available from:. https://www.novartis.com/news/media-releases/novartis-receives-us-food-and-drug-administration-fda-orphan-drug-designation-branaplam-lmi070-huntington%27s-disease-hd (Accessed on 2021 June 12).
[54]
Bordet T, Berna P, Abitbol JL, Pruss RM. Olesoxime (TRO19622): A novel mitochondrial-targeted neuroprotective compound. Pharmaceuticals (Basel) 2010; 3(2): 345-68.
[http://dx.doi.org/10.3390/ph3020345] [PMID: 27713255]
[55]
Weber JJ, Clemensson LE, Schiöth HB, Nguyen HP. Olesoxime in neurodegenerative diseases: Scrutinising a promising drug candidate. Biochem Pharmacol 2019; 168: 305-18.
[http://dx.doi.org/10.1016/j.bcp.2019.07.002] [PMID: 31283931]
[56]
Bertini E, Dessaud E, Mercuri E, et al. Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: A randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2017; 16(7): 513-22.
[http://dx.doi.org/10.1016/S1474-4422(17)30085-6] [PMID: 28460889]
[57]
Rudnicki SA, Andrews JA, Duong T, et al. Reldesemtiv in patients with spinal muscular atrophy: A phase 2 hypothesisgenerating study. neurotherapeutics. 2021. Available from:. https://link.springer.com/article/10.1007%2Fs13311-020-01004-3 (Accessed on 2021 June 13).
[58]
Long KK, O’Shea KM, Khairallah RJ, et al. Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy. Hum Mol Genet 2019; 28(7): 1076-89.
[http://dx.doi.org/10.1093/hmg/ddy382] [PMID: 30481286]
[59]
Biogen plans to initiate phase 4 study evaluating benefit of spinraza ® (nusinersen) in patients treated with zolgensma® (onasemnogene abeparvovec). Biogen Available from:. https://investors. biogen.com/news-releases/news-release-details/biogen-plans-initiate-phase-4-study-evaluating-benefit-spinrazar (Accessed on 2021 Jun 13).
[60]
Zhou H, Meng J, Malerba A, et al. Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy. J Cachexia Sarcopenia Muscle 2020; 11(3): 768-82.
[http://dx.doi.org/10.1002/jcsm.12542] [PMID: 32031328]

Rights & Permissions Print Cite
Article Metrics
62
1
© 2024 Bentham Science Publishers | Privacy Policy