Recent therapeutic developments in spinal muscular atrophy

Recent therapeutic developments in spinal muscular atrophy

Proximal spinal muscular atrophy (SMA) is an inherited neurodegenerative disease with a heterogeneous clinical phenotype.Although there is no cure for SMA, several strategies are currently being developed. In this review, we summarize the ongoing clinicaltrials and molecular mechanisms of successful approaches to SMA treatment.

___

  • Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin 2015; 33; 4: 831-846.
  • Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, Flynn K, Hendrickson BC, Scholl T, Sirko-Osadsa DA et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet 2012; 20: 27-32.
  • Farrar MA, Park SB, Vucic S, Carey KA, Turner BJ, Gillingwater TH, Swoboda KJ, Kiernan MC. Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol 2017; 81: 355-368.
  • Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol 2007; 22: 1027-1049.
  • Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995; 80: 155-165.
  • Ogino S, Wilson RB. Spinal muscular atrophy: molecular genetics and diagnostics. Expert Rev Mol Diagn 2004; 4: 15-29.
  • Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000; 15: 228-237.
  • Erdem H, Pehlivan S, Topaloğlu H, Ozgüç M. Deletion analysis in Turkish patients with spinal muscular atrophy. Brain Dev 1999; 21: 86-89.
  • Burghes AHM. When is a deletion not a deletion? When it is converted. Am J Hum Genet 1997; 61: 9-15.
  • 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: 6307-6311.
  • Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH, McPherson JD. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999; 8: 1177- 1183.
  • Frugier T, Nicole S, Cifuentes-Diaz C, Melki J. The molecular bases of spinal muscular atrophy. Curr Opin Genet Dev 2002; 12: 294-298.
  • Wirth B, Brichta L, Hahnen E. Spinal muscular atrophy: from gene to therapy. Semin Pediatr Neurol 2006; 13: 121-131.
  • Rochette CF, Gilbert N, Simard LR. SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum Genet 2001; 108: 255-266.
  • Agrawal M, Vercelli A, Mielcarek M, Butchbach MER. Copy number variations in the Survival Motor Neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci 2016; 3: 7.
  • Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther 2017; 24: 529-533.
  • Bora-Tatar G, Yesbek-Kaymaz A, Bekircan-Kurt CE, ErdemÖzdamar S, Erdem-Yurter H. Spinal muscular atrophy type III: molecular genetic characterization of Turkish patients. Eur J Med Genet 2015; 58: 654-658.
  • Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, Burghes AH, Kissel JT. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet 2009; 3: 408-413.
  • Nölle A, Zeug A, van Bergeijk J, Tönges L, Gerhard R, Brinkmann H, Al Rayes S, Hensel N, Schill Y, Apkhazava D et al. The spinal muscular atrophy disease protein SMN is linked to the Rhokinase pathway via profilin. Hum Mol Genet 2011; 20: 4865-4878.
  • Hensel N, Stockbrügger I, Rademacher S, Broughton N, Brinkmann H, Grothe C, Claus P. Bilateral crosstalk of rhoand extracellular-signal-regulated-kinase (ERK) pathways is confined to a unidirectional mode in spinal muscular atrophy (SMA). Cell Signal 2014; 26: 540-548.
  • Bowerman M, Shafey D, Kothary R. SMN depletion alters profilin II expression and leads to upregulation of the RhoA/ROCK pathway and defects in neuronal integrity. J Mol Neurosci 2007; 32: 120-131.
  • Oprea GE, Kröber S, McWhorter ML, Rossoll W, Müller S, Krawczak M, Bassell GJ, Beattie CE, Wirth B. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 2008; 320: 524-527.
  • Rossoll W, Kröning A-K, Ohndorf U-M, Steegborn C, Jablonka S, Sendtner M. Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/ hnRNP-Q: a role for Smn in RNA processing in motor axons? Hum Mol Genet 2002; 11: 93-105.
  • Riessland M, Kaczmarek A, Schneider S, Swoboda KJ, Löhr H, Bradler C, Grysko V, Dimitriadi M, Hosseinibarkooie S, Torres-Benito L et al. Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis. Am J Hum Genet 2017; 100: 297- 315.
  • Boyer JG, Bowerman M, Kothary R. The many faces of SMN: deciphering the function critical to spinal muscular atrophy pathogenesis. Future Neurol 2010; 5: 873-890.
  • Hensel N, Claus P. The actin cytoskeleton in SMA and ALS: how does it contribute to motoneuron degeneration? Neurosci 2018; 24: 54-72.
  • Coady TH, Lorson CL. SMN in spinal muscular atrophy and snRNP biogenesis. Wiley Interdiscip Rev RNA 2011; 2: 546-564.
  • Singh RN, Howell MD, Ottesen EW, Singh NN. Diverse role of survival motor neuron protein. Biochim Biophys Acta - Gene Regul Mech 2017; 1860: 299-315.
  • Bowerman M, Swoboda KJ, Michalski JP, Wang GS, Reeks C, Beauvais A, Murphy K, Woulfe J, Screaton RA, Scott FW et al. Glucose metabolism and pancreatic defects in spinal muscular atrophy. Ann Neurol 2012; 72: 256-268.
  • Boyer JG, Murray LM, Scott K, De Repentigny Y, Renaud JM, Kothary R. Early onset muscle weakness and disruption of muscle proteins in mouse models of spinal muscular atrophy. Skelet Muscle 2013; 3: 24.
  • Shababi M, Habibi J, Yang HT, Vale SM, Sewell WA, Lorson CL. Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum Mol Genet 2010; 19: 4059-4071.
  • Deguise MO, Kothary R. New insights into SMA pathogenesis: immune dysfunction and neuroinflammation. Ann Clin Transl Neurol 2017; 4: 522-530.
  • Wirth B, Barkats M, Martinat C, Sendtner M, Gillingwater TH. Moving towards treatments for spinal muscular atrophy: hopes and limits. Expert Opin Emerg Drugs 2015; 20: 353-356.
  • Bowerman M, Becker CG, Yáñez-Muñoz RJ, Ning K, Wood MJA, Gillingwater TH, Talbot K; UK SMA Research Consortium. Therapeutic strategies for spinal muscular atrophy: SMN and beyond. Dis Model Mech 2017; 10: 943-954.
  • Wertz MH, Sahin M. Developing therapies for spinal muscular atrophy. Ann N Y Acad Sci 2016; 1366: 5-19.
  • Scoto M, Finkel RS, Mercuri E, Muntoni F. Therapeutic approaches for spinal muscular atrophy (SMA). Gene Ther 2017; 24: 514-519.
  • Wood MJA, Talbot K, Bowerman M. Spinal muscular atrophy: antisense oligonucleotide therapy opens the door to an integrated therapeutic landscape. Hum Mol Genet 2017; 26: R151-R159.
  • Dayangac-Erden D, Bora-Tatar G, Dalkara S, Demir AS, ErdemYurter H. Carboxylic acid derivatives of histone deacetylase inhibitors induce full length SMN2 transcripts: A promising target for spinal muscular atrophy therapeutics. Arch Med Sci 2011; 7: 230-234.
  • Uzunalli G, Bora-Tatar G, Dayangaç-Erden D, Erdem-Yurter H. Effects of flavonoid quercetin on survival of motor neuron gene expression. Cell Biol Int 2015; 39: 350-354.
  • Dayangaç-Erden D, Bora G, Ayhan P, Kocaefe C, Dalkara S, Yelekçi K, Demir AS, Erdem-Yurter H. Histone deacetylase inhibition activity and molecular docking of (e)-resveratrol: its therapeutic potential in spinal muscular atrophy. Chem Biol Drug Des 2009; 73: 355-364.
  • Avila A, Burnett B. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J Clin 2007; 117: 659-671.
  • Riessland M, Ackermann B, Förster A, Jakubik M, Hauke J, Garbes L, Fritzsche I, Mende Y, Blumcke I, Hahnen E et al. SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy. Hum Mol Genet 2010; 19: 1492- 1506.
  • Sumner CJ, Huynh TN, Markowitz JA, Perhac JS, Hill B, Coovert DD, Schussler K, Chen X, Jarecki J, Burghes AH et al. Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann Neurol 2003; 54: 647-654.
  • Calder AN, Androphy EJ, Hodgetts KJ. Small molecules in development for the treatment of spinal muscular atrophy. J Med Chem 2016; 59: 10067-10083.
  • Porensky PN, Burghes AHM. Antisense oligonucleotides for the treatment of spinal muscular atrophy. Hum Gene Ther 2013; 24: 489-498.
  • Singh NN, Howell MD, Androphy EJ, Singh RN. How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther 2017; 24: 520-526.
  • Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC, Norris DA, Bennett CF, Bishop KM. Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology 2016; 86: 890-897.
  • Mulcahy PJ, Iremonger K, Karyka E, Herranz-Martín S, Shum KT, Tam JK, Azzouz M. Gene therapy: a promising approach to treating spinal muscular atrophy. Hum Gene Ther 2014; 25: 575-586.
  • DiDonato CJ, Parks RJ, Kothary R. Development of a gene therapy strategy for the restoration of survival motor neuron protein expression: implications for spinal muscular atrophy therapy. Hum Gene Ther 2003; 14: 179-188.
  • Meyer K, Ferraiuolo L, Schmelzer L, Braun L, McGovern V, Likhite S, Michels O, Govoni A, Fitzgerald J, Morales P et al. Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose–response study in mice and nonhuman primates. Mol Ther 2015; 23; 3: 477-487.
  • Bertini E, Dessaud E, Mercuri E, Muntoni F, Kirschner J, Reid C, Lusakowska A, Comi GP, Cuisset JM, Abitbol JL et al. Safety and efficacy of olesoxime in patients with type 2 or nonambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2017; 16: 513-522.
  • Lewelt A, Krosschell KJ, Stoddard GJ, Weng C, Xue M, Marcus RL, Gappmaier E, Viollet L, Johnson BA, White AT et al. Resistance strength training exercise in children with spinal muscular atrophy. Muscle Nerve 2015; 52: 559-567.
  • Grondard C, Biondi O, Armand AS, Lécolle S, Della Gaspera B, Pariset C, Li H, Gallien CL, Vidal PP, Chanoine C et al. Regular exercise prolongs survival in a type 2 spinal muscular atrophy model mouse. J Neurosci 2005; 25: 7615-7622.
  • Evers MM, Toonen LJA, van Roon-Mom WMC. Antisense oligonucleotides in therapy for neurodegenerative disorders. Adv Drug Deliv Rev 2015; 87: 90-103.
  • Singh NK, Singh NN, Androphy EJ, Singh RN. Splicing of a critical exon of human survival motor neuron is regulated by a unique silencer element located in the last intron. Mol Cell Biol 2006; 26: 1333-1346.
  • Singh NN, Lee BM, DiDonato CJ, Singh RN. Mechanistic principles of antisense targets for the treatment of spinal muscular atrophy. Future Med Chem 2015; 7: 1793-1808.
  • Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NLJK, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu MT et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017; 377: 1723-1732.
  • Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 2016; 388: 3017-3026.
  • Dowling JJ, D Gonorazky H, Cohn RD, Campbell C. Treating pediatric neuromuscular disorders: the future is now. Am J Med Genet A 2017: 1-38.
  • Le TT, McGovern VL, Alwine IE, Wang X, Massoni-Laporte A, Rich MM, Burghes AH. Temporal requirement for high SMN expression in SMA mice. Hum Mol Genet 2011; 20: 3578-3591.
  • Tizzano EF, Finkel RS. Spinal muscular atrophy: A changing phenotype beyond the clinical trials. Neuromuscular Disord 2017; 27: 883-889.
  • Sumner CJ. Therapeutics development for spinal muscular atrophy. NeuroRx. 2006; 3: 235-245.
  • Bordet T, Buisson B, Michaud M, Drouot C, Galéa P, Delaage P, Akentieva NP, Evers AS, Covey DF, Ostuni MA et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther 2007; 322: 709-720.
  • Bordet T, Berna P, Abitbol JL, Pruss RM. Olesoxime (TRO19622): a novel mitochondrial-targeted neuroprotective compound. Pharmaceuticals 2010; 3: 345-368.
  • Hwang PM, Sykes BD. Targeting the sarcomere to correct muscle function. Nat Rev Drug Discov 2015; 14: 313-328. 66. Gomes AV, Potter JD, Szczesna-Cordary D. The role of troponins in muscle contraction. IUBMB Life 2002; 54: 323- 333.
  • Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, Van Hoosear M, Shin Y, Chin DN, Keller CG et al. SMN2 splice modulators enhance U1–pre-mRNA association and rescue SMA mice. Nat Chem Biol 2015; 11: 511-517.
  • Tsai LK, Tsai MS, Ting CH, Li H. Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice. J Mol Med (Berl) 2008; 86: 1243-1254.
  • Maggi L, Mantegazza R. Treatment of myasthenia gravis: focus on pyridostigmine. Clin Drug Investig 2011; 31: 691-701.
  • Farooq F, Abadía-Molina F, MacKenzie D, Hadwen J, Shamim F, O’Reilly S, Holcik M, MacKenzie A. Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation. Hum Mol Genet 2013; 22: 3415-3424.
  • Yeşbek-Kaymaz A, Bora-Tatar G, Erdem-Yurter H. Contribution of skeletal muscle defects in spinal muscular atrophy. Acta Med 2015; 4: 51-58.
  • Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 2010; 28: 271- 274.
  • Valori CF, Ning K, Wyles M, Mead RJ, Grierson AJ, Shaw PJ, Azzouz M. Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci Transl Med 2010; 2: 35ra42.
  • Passini MA, Bu J, Roskelley EM, Richards AM, Sardi SP, O’Riordan CR, Klinger KW, Shihabuddin LS, Cheng SH. CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy. J Clin Invest 2010; 120: 1253-1264.
  • Glascock JJ, Osman EY, Wetz MJ, Krogman MM, Shababi M, Lorson CL. Decreasing disease severity in symptomatic, Smn(– /–); SMN2(+/+), spinal muscular atrophy mice following scAAV9-SMN delivery. Hum Gene Ther 2012; 23: 330-335.
  • Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 377: 1713-1722.