Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
The development of therapies focused on treating or preventing spinal muscular atrophy (SMA) is challenged by the different phenotypes of the disease and the variety of presentations. But a major effort from the scientific community has resulted in significant advances in the understanding of SMA pathophysiology and subsequent identification of potential therapeutic targets.
While 3 US Food and Drug Administration (FDA) approved drugs are available, the treatment of SMA also requires a multidisciplinary team and approach. SMA treatment is not only based in pharmacology but also encompasses rehabilitation of patients’ respiratory and orthopedic functions. Nutritional and psychological support are also important treatment components.1,2
The pharmacological treatment of SMA is based in survival motor neuron (SMN)- dependent therapies and SMN-independent therapies.2,3 The first group includes drugs that actively target SMN2 splicing,3 as well as drugs that replace the SMN1 gene. These are highlighted as the best strategies to delay the degeneration of motor neurons.
Nusinersen (SpinrazaⓇ) is an antisense oligonucleotide (ASO) approved by the FDA in 2016 that promotes the upregulation of the SMN protein.4 Nusinersen acts on SMN2 splicing that increases exon 7 inclusion in the mRNA transcript and consequently increases the formation of fully functional SMN protein.4 It was the first drug approved for SMA treatment in children and adults. Due to the drug’s inability to cross the blood-brain barrier (BBB), patients receive the drug intrathecally.2
Read more about nusinersen.
SMN Splicing Modifiers
Risdiplam (Evrysdi™) is a small molecule and a modulator of the SMN2 splicing that reduces the development of off-target effects.6 Adults and children aged 2 months and older who are diagnosed with SMA type 1, 2, or 3 may benefit from this drug.2,3,5 Because risdiplam is able to cross the BBB, it can be given orally. Other orally administered drugs such as branaplam (LM1070, Novartis) are in clinical development.5
Read more about risdiplam.
Gene Replacement Therapy
Onasemnogene abeparvovec-xioi (ZolgensmaⓇ) is a form of SMN1 gene replacement. The goal of this SMN-dependent therapy is to deliver intact copies of the SMN1 gene into cells so that a fully functional SMN protein can be expressed in adequate levels.2,3 Onasemnogene abeparvovec enters through cells, including those in the central nervous system, using a nonreplicating adeno-associated virus capsid, scAAV9. The use of onasemnogene abeparvovec is indicated for patients aged less than 2 years presenting biallelic mutations of the SMN1 gene.3
An important drawback for the use of this drug is that a minority of patients have AAV9-neutralizing antibodies that can reduce the efficacy of the therapy and potentially increase the risk of immunogenicity and adverse effects.7 The concentration of anti-AAV antibodies that might prevent successful gene expression is not clear. In clinical trials and in practice, a conservative antibody threshold of 1:50 has been used to determine patient eligibility.
Read more about onasemnogene abeparvovec-xioi.
Other Pharmacological Treatment Options
Therapeutic approaches that are SMN-independent are targeting different groups of cells with the goal of function improvement. These strategies aim to fill the lack of options for patients who do not benefit from gene therapy or for whom issues of therapeutic accessibility associated with treatment location or cost arise. Ideally, these therapies should be used in a combinatorial approach with SMN- dependent strategies. SMN-independent approaches are still under evaluation for SMA use and include neuroprotective treatments such as gabapentin, olesoxime, and riluzole, and muscle-enhancing therapies such as reldesemtiv.8,9,10 However, no clinical benefits have been observed in several completed trials.11,12
Patients with SMA type 1 or 2 are prone to the development of muscular and orthopedic complications such as joint contractures.13 Dislocated or subluxated hips are common but surgical management has proven to deliver reduced benefits.14
Scoliosis and spinal deformities are prevalent in many patients with SMA type 1 to type 35 and surgery might allow a successful curve correction.14 Surgery may also ease pressure sores and allow patients to sit with more comfort,14 however, opting for a surgical treatment is dependent on each patient, the severity of the disease, and the degree of pain each patient is experiencing.
Endotracheal intubation of SMA patients is frequently needed.17 As the muscular weakness typically observed in SMA patients limits the ability to open the mouth widely, this medical procedure can be difficult to perform.18 However, noninvasive ventilation (NIV) can be used with SMA patients beginning in early infancy to help improve quality of life.17
Other surgical interventions include the placement of feeding tubes such as gastrostomy tubes. As SMA patients present with feeding and swallowing difficulties, this intervention allows increased control of the complications arising from weight loss and malnutrition.1,19
Physical Therapy and Exercise
There is no widely accepted recommendation concerning exercise in SMA. Studies have concluded that daily exercise is safe for ambulatory patients and should be encouraged.15 Physical therapy and aerobic exercises can be used to increase and stabilize muscle strength as well as improve motor function.16 Exercise benefits, especially from aerobic training, are difficult to assess in SMA patients, but may include an improved psychological state, reduced depression, and a higher quality of life.
Reviewed by Michael Sapko, MD on 7/1/2021
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2. Messina S, Sframeli M. New treatments in spinal muscular atrophy: positive results and new challenges. J Clin Med. 2020;9(7):2222. doi:10.3390/jcm9072222
3. Ojala KS, Reedich EJ, DiDonato CJ, Meriney SD. In search of a cure: the development of therapeutics to alter the progression of spinal muscular atrophy. Brain Sci. 2021;11(2):194. doi:10.3390/brainsci11020194
4. Mercuri E, Pera MC, Scoto M, Finkel R, Muntoni F. Spinal muscular atrophy — insights and challenges in the treatment era. Nat Rev Neurol. 2020;16(12):706-715. doi:10.1038/s41582-020-00413-4
5. Menduti G, Rasà DM, Stanga S, Boido M. Drug screening and drug repositioning as promising therapeutic approaches for spinal muscular atrophy treatment. Front Pharmacol. 2020;11:592234. doi:10.3389/fphar.2020.592234
6. Sivaramakrishnan M, McCarthy KD, Campagne S, et al. Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. Nat Commun. 2017;8:1476. doi:10.1038/s41467-017-01559-4
7. Sumner CJ, Crawford TO. Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain. J Clin Investig. 2018;128(8):3219-3227. doi:10.1172/JCI121658
8. Cheng AJ, Hwee DT, Kim LH, et al. Fast skeletal muscle troponin activator CK-2066260 increases fatigue resistance by reducing the energetic cost of muscle contraction. J Physiol. 2019;597:4615-4625. doi:10.1113/JP278235
9. Miller RG, Moore DH, Dronsky V, et al. A placebo-controlled trial of gabapentin in spinal muscular atrophy. J Neurol Sci. 2001;191(1-2):127-131. doi:10.1016/S0022-510X(01)00632-3
10. Muntoni F, Bertini E, Comi G, et al. Long-term follow-up of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA) treated with olesoxime in the OLEOS trial. Neuromuscul Disord. 2020;30(12):959-969. doi:10.1016/j.nmd.2020.10.008
11. Abbara C, Estournet B, Lacomblez L, et al. Riluzole pharmacokinetics in young patients with spinal muscular atrophy. Br J Clin Pharmacol. 2011;71(3):403-410. doi:10.1111/j.1365-2125.2010.03843.x
12, Merlini L, Solari A, Vita G, et al. Role of gabapentin in spinal muscular atrophy: results of a multicenter, randomized Italian study. J Child Neurol. 2003;18(8):537-541. doi:10.1177/08830738030180080501
13. Salazar R, Montes J, et al. Quantitative evaluation of lower extremity joint contractures in spinal muscular atrophy: implications for motor function. Pediatr Phys Ther. 2018;30(3):209-215. doi:10.1097/PEP.0000000000000515
14. Mesfin A, Sponseller P, Leet A. Spinal muscular atrophy: manifestations and management. J Am Acad Orthop Surg. 2012;20(6):393-401. doi:10.5435/JAAOS-20-06-393
15. Montes J, Garber CE, Kramer SS, et al. Single-blind, randomized, controlled clinical trial of exercise in ambulatory spinal muscular atrophy: why are the results negative? J Neuromuscul Dis. 2015;2(4):463-470. doi:10.3233/JND-150101
16. Iftikhar M, Frey J, Shohan M, Malek S, Mousa SA. Current and emerging therapies for Duchenne muscular dystrophy and spinal muscular atrophy. Pharmacol Ther. 2021;220:107719. doi:10.1016/j.pharmthera.2020.107719
17. Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol. 2012;11:443-452. doi:10.1016/S1474-4422(12)70061-3
18. Wijngaarde CA, Stam M, de Kort FAS, Wadman RI, van der Pol WL. Limited maximal mouth opening in patients with spinal muscular atrophy complicates endotracheal intubation: an observational study. Eur J Anaesthesiol. 2018;35(8):629-631. doi:10.1097/EJA.000000000000083819. Durkin ET, Schroth MK, Helin M, Shaaban AF. Early laparoscopic fundoplication and gastrostomy in infants with spinal muscular atrophy type I. J Pediatr Surg. 2008;243(11):2031-2037. doi:10.1016/j.jpedsurg.2008.05.035