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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