Spinal Muscular Atrophy: Current Medications and Re-purposed Drugs

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive genetic neuromuscular disorder that is characterized by gradual muscle weakness and atrophy due to the degeneration of alpha motor neurons that are present on the anterior horn of the spinal cord. Despite the comprehensive investigations conducted by global scientists, effective treatments or interventions remain elusive. The time- and resource-intensive nature of the initial stages of drug research underscores the need for alternate strategies like drug repurposing. This review explores the repurposed drugs that have shown some improvement in treating SMA, including branaplam, riluzole, olesoxime, harmine, and prednisolone. The current strategy for medication repurposing, however, lacks systematicity and frequently depends more on serendipitous discoveries than on organized approaches. To speed up the development of successful therapeutic interventions, it is apparent that a methodical approach targeting the molecular origins of SMA is strictly required.

Introduction

Spinal muscular atrophy (SMA) is a genetic disorder that is autosomal recessive in nature and occurs as a result of the degeneration of alpha motor neurons (α-MNs) within the anterior horn of the spinal cord that primarily affects the lower extremities and is characterized by hypotonia, muscular atrophy, weakness of the proximal muscles, and respiratory insufficiency, which frequently results in death in the most severe cases (Lunn and Wang 2008). The most frequent symptoms are flaccid or weak arms and legs, movement issues (difficulties in sitting up, crawling, or walking), tremors (twitching or shaking muscles), bone and joint issues (such as an abnormally curved spine known as scoliosis), swallowing issues, and breathing difficulties. Based on the age of onset of the disease and degree of motor function, SMA has five subtypes. A homozygous deletion or mutation within the 5q13 survival motor neuron 1 (SMN1) gene causes the autosomal-recessive form of SMA, which is responsible for almost 95% of cases of SMA (Menduti et al. 2020).

SMA is an extremely severe neuromuscular disease that affects one in 3900–16,000 live births and primarily affects children and young people. From the year 2011 to 2015, 4653 patients in Europe received a genetic diagnosis and 992 of those diagnoses came in 2015 alone (Chong et al. 2021). The incidence of SMA is roughly 10 per 100,000 live births. Estimates ranged from 5 to 24 in 100,000 births, according to a recent assessment. Given the significantly reduced life expectancy associated with the most frequent type of SMA, the prevalence has been estimated to be between 1 and 2 in 100,000 people (Lally et al. 2017).

The occurrence of the disease in a newborn depends on the genetics of its. Being an inherited disease, its prevention is challenging and symptoms often occur in early childhood. The existing therapeutics of SMA targets either enhance the production of the SMN2 gene or restore the SMN1 gene. However, the effectiveness of the drugs is bounded and is determined by the genetics, subtype of SMA, age of the patient, dose and administration of drugs. Hence, there exists continuous efforts for better treatment of SMA which include discovery of new drugs as well as repurposed use of existing drugs.

In this context, this review seeks to offer a comprehensive perspective on SMA, beginning with an exploration of its subtypes and molecular underpinnings, followed by an examination of the evolving understanding of the disease. We have also discussed the current drugs, their limitations, and further concentrated on the repurposed drugs targeting SMA. All these efforts lead to different clinical and pre-clinical studies related to SMA and may provide future medications. We finally conclude the requirement of a comprehensive strategy and methodological molecular approaches for improving SMA treatment.

Types and Molecular Basis of SMA

In 1991, the Muscular Dystrophy Association sponsored the International Consortium on Spinal Muscular Atrophy which standardized the various phenotypes that had been reported into a classification system (Menduti et al. 2020). Based on the age of onset and the maximum degree of motor function, three categories of SMA were identified in this classification. A fourth type of SMA was added later and included adult-onset cases. It also introduced a type 0 for patients who died within weeks of onset in pregnancy (Farooq et al. 2013). Neonatal with a history of reduced fetal movements and significant weakness and hypotonia are classified as SMA type 0. The type 1 SMA also known as Werdnig– Hoffman disease or ‘non-sitters’ which pertains to infants who are younger than 6 months is characterized by hypotonia, impaired head control, and diminished or absent tendon reflexes (Keinath et al. 2021). Children who have type 2 SMA also known as ‘sitters’ can sit without assistance during the stages of development but they are unable to walk on their own. Progression of proximal weakness in the legs is greater than arm weakness and it is a common indication of this form of SMA (Zerres and Davies 1999). The third type of SMA, which is type 3 also commonly known as Kugelberg-Welander illness, affects both adults and children. During their lifespan, affected individuals can walk without assistance for some period of time (Zerres et al. 1997). They are known as ‘walkers’. Individuals with SMA type 4 are considered to be at the mild end of the spectrum. They exhibit the mildest version of SMA and account for a mere five percent of cases. These people can move around and resemble type 3; The onset for this type usually occurs in adulthood although it can have a juvenile origin (Chong et al. 2021). Figure 1 illustrates different types of SMA.

Fig. 1.

Schematic showing different types of SMA along with their age of onset and possible lifespan of patients

α-MNs are present within the anterior horn of the spinal cord which is degenerated in people with SMA which is a monogenic autosomal recessive genetic condition (Kolb and Kissel 2011; Otsuki 2018). Symmetric muscular weakening and atrophy result from the progressive loss of α-MNs, which triggers muscle contraction (Crawford and Pardo 1996; Markowitz et al. 2004). In most of the cases, the major symptoms of the SMA disease lead to paralysis or even death. The lower muscles also known as the proximal muscles are impacted first, followed by the upper extremities (Tisdale and Pellizzoni 2015; Mahajan 2019). Given that the functional loss starts at the beginning of the disease and then gradually worsens over time, the condition has a unique genetic background (Sumner and Crawford 2018).

The survival motor neuron 1 (SMN1) gene, located on chromosome 5q13 which acts as the genetic blueprint for the SMN protein, is deleted or mutated in approximately 95% of the SMA cases (Chong et al. 2021). All eukaryotic creatures have a single copy of the highly conserved SMN1 gene in their genomes (Bowerman et al. 2017). Humans have two SMN genes SMN1 and SMN2. SMN1, in its telomeric form, translates to a protein known as full-length SMN, or FL-SMN. SMN2 in its centromeric homologous form, primarily produces the truncated and quickly degraded protein delta7-SMN (SMNΔ7) and only approximately 10% of FL-SMN (Sumner and Crawford 2018). Apart from five variations in base pairs, the genes exhibit nearly identical sequences. They encode the same SMN protein, though, and the base pair variations do not change the amino acid sequence (Chong et al. 2021).

The functional, full-length SMN (FL-SMN) protein is produced by the SMN1 gene. There is a synonymous C-to-T nucleotide alteration at position 6 in SMN2 exon 7 which causes improper splicing, resulting in around ninety percent of exon 7’s transcript being skipped (Cartegni and Krainer 2002; Kashima and Manley 2003; Farooq et al. 2013). An unstable and shortened SMN protein is produced when such a transcript is subsequently translated (Chong et al. 2021). While patients with any form of SMA lack a functional SMN1 gene and are solely dependent on the SMN2 gene, only ~ 5–10% of FL-SMN protein will be produced by the SMN2 gene. This means that they are lacking in the synthesis of SMN proteins, which causes the spinal cord to lose motor neurons (MNs). Among five different types of SMA, an increased number of SMN2 copies is associated with milder phenotypes (Menduti et al. 2020). Figure 2 illustrates the pathogenesis of SMA.

Fig. 2.

Genetic basis of SMA. Both SMN1 and SMN2 genes, located at chromosome 5 can produce SMN protein which is essential for motor neuron functioning. In SMA patients the SMN1 gene is mutated at exon 7 due to which the SMN1 gene cannot produce SMN protein. The SMN2 gene produces a less stable SMN protein if there is C to T transition at exon 7

Past and Present Status of SMA

SMA has a history that spans more than a century and is thoroughly documented. French neurologist Aran and British neurologist Werdnig independently reported newborns with progressive muscle weakness and wasting caused by a spinal cord disease in the late nineteenth century, which is when the first records of SMA were made. The phrase “infantile progressive muscular atrophy,” was first used by Aran, and is commonly used to refer to SMA type 1. Werdnig’s results established the groundwork for additional research on the genetic origin of SMA by highlighting the hereditary character of the ailment (Nishio 2023). In addition to that German neurologist Johann Hoffmann made a substantial contribution to the field of SMA study at the beginning of the twentieth century when he discovered family cases of SMA that impacted several generations. These cases are currently referred to as SMA type 3 or Kugelberg-Welander illness (Nishio 2023). Techniques like Electromyography (EMG) have helped to better understand the clinical symptoms of SMA and improve SMA diagnosis (Sumner and Crawford 2018). It was discovered later that the SMN2 gene also modifies the severity of SMA.

Treatment for SMA has shown significant advancements in recent years. the first disease-modifying therapy, nusinersen (Spinraza), was approved in 2016 (Menduti et al. 2020) followed by onasemnogene abeparvovec (Zolgensma), a gene replacement therapy in 2019. In addition, the first oral drug risdiplam has been developed for SMA It is authorized for treating SMA in patients aged 2 months and older (Lunn and Wang 2008). These historical turning points in the study of SMA have paved the way for the current developments, advancing the hunt for efficient therapies and a comprehensive understanding of this life-threatening disorder.

Current Drugs of SMA and Their Limitations

Despite the fact that SMA is a severe disease with recognized genetic origins, there was still no cure for it until 2017. In fact, the scientific, pharmaceutical, academic, and clinical communities worked together to find efficient medications that could either raise the production of the SMN2 gene or restore SMN1, thereby making up for the absence of FL-SMN protein (Menduti et al. 2020).

The first medication for both adults and newborns with SMA to be approved by the European Medicines Agency (EMA) in June 2017 and the Food and Drug Administration (FDA) in December 2016 is Biogen’s nusinersen (Spinraza). It is a modified 2′-O-methoxyethyl antisense oligonucleotide (ASO) intended to boost the SMN protein’s expression (Chiriboga et al. 2016). The drug nusinersen improves the ability of SMN2 to produce FL-SMN by joining the intron-splicing silencer region N1 which is present in the SMN2 pre-messenger RNA assisting the inclusion of exon seven (Shorrock et al. 2018). However, the drug must be administered intrathecally because it does not have the capability to cross the blood-brain barrier (BBB).

The FDA approved another drug for SMA, AVXS-101 (Zolgensma) from AveXis, a Novartis company, after positive results from the phase one START study (NCT01547871) were published, in May 2019. The study focused on the drug’s safety and efficacy following a single infusion in patients with SMA type 1 who had symptoms before the age of six months (Zolgensma | European Medicines Agency n.d.). The non-replicating recombinant AAV9, which is known as AVXS-101 carries the complementary DNA of the human SMN gene and it is regulated by the chicken β-actin hybrid promoter.

Risdiplam is another drug that was approved by the FDA on August 7th, 2020 for the treatment of SMA in adults and children 2 months and older (Dhillon 2020). It is an mRNA splicing modifier that raises the expression of the SMN protein. It is an oral liquid treatment that does not require hospital admission (Genentech: Press Releases | Friday 2020). There are presently four open-label trials studying risdiplam. In addition to the data that has been generated about the safety profile of all the listed treatments and their notable advantages for specific groups of SMA patients, it is imperative to consider the limits of these medications, both from a medical and socio-economic perspective (Genentech: Press Releases | Friday 2020) (Table 1).

Table 1.

List of current drugs used in SMA treatment

Sl. no	Name of the drugs	Mode of administration
1	Nusinersen	It is intrathecally administered as it cannot pass BBB
2	AVXS-101 (Onasemnogene abeparvovec)	Intravenous infusion
3	Risdiplam	Orally

A significant drawback of the currently available treatments for SMA is that they only focus on SMN-dependent approaches, disregarding additional molecular pathways like Mitochondria-Related Pathways, Cell Death and Degradation Pathways that could contribute to the pathophysiology of the disease (Chong et al. 2021). Combinational remedies should be explored in order to address this concern which could be done by redefining the parameters and time of the administration of the existing SMN-enhancing therapies as well as considering their synergistic effects with other medications. In general, to address the SMN-independent aspects of SMA pathogenesis, combinatorial therapeutic approaches are needed (Menduti et al. 2020).

Furthermore, the effectiveness of the available treatments is strictly correlated with the age and type of patients; that is to say, early-treatment patients exhibit the most consistent effects of SMN-enhancing therapies, whereas delayed intervention results in less effective or no motor neuron defect rescue (Hoolachan et al. 2019). Indeed, SMN-restoring interventions appear to be especially successful in the early stages of SMA disease when muscle functions are still intact and the MNs are still alive (Hensel et al. 2020). Nusinersen and AVXS-101 can greatly increase the survival of infants with SMA type 1, enabling them to reach motor milestones, depending on their age at the start of therapy; young patients with SMA type 2 also exhibited improvements on many motor scales following treatment. These treatments not only worked for SMA type 1 patients but also young patients with SMA type 2 exhibited some progress on different motor scales. Yet, the improvements did not reach similarly significant levels when nusinersen was delivered to adult patients with SMA type 2 and 3 (20–68 years old). Instead, these medications could only help stabilize motor performance and slow the progression of symptoms for this group (Menduti et al. 2020; Chong et al. 2021).

It should be noted that the available treatments have other drawbacks. These drugs along with their way of administration might cause some serious side effects which can be harmful. The cost and the accessibility of these medications are also concerning. Additionally, serious scoliosis and spinal abnormalities are often developed by SMA patients, which further complicates or impedes this mode of administration (Poletti and Fischbeck 2020). These complications can be avoided by the development of systemically or orally administered drugs like AVXS-101 or risdiplam (Poletti and Fischbeck 2020).

Thus far, several orally administered compounds are undergoing the last stages of clinical development and trials. These encompass an mRNA splicing corrector known as branaplam (LMI070, Novartis), and a swift-skeletal muscle troponin activator, reldesemtiv (CK-2127107, Cytokinetics) (Poletti and Fischbeck 2020; Ramdas and Servais 2020). The alternative routes of administration additionally ensure the restoration of peripheral SMN, which complements the central effects of SMN.

Furthermore, serious side effects from the existing medications include headache, back discomfort (nusinersen), bleeding, acute liver injury, and heart damage (AVXS-101). Additionally, 5% of patients treated with AVXS-101 may produce anti-AAV9 antibodies, which may decrease the therapeutic efficacy of the gene therapy and raise the likelihood of an immunological response (Al-Zaidy and Mendell 2019). It is clear from the restrictions placed on the licensed medications for SMA that further research into possible treatments is required.

Drug Repurposing in SMA

Several limitations of current drugs have led to the requirement of new drugs for SMA. However, drug development through traditional methods is a difficult, risky, time-consuming, and expensive procedure. It requires computational approach, drug metabolic analysis, random screening, molecular manipulation, and serendipitous research (Myers and Baker 2001). It involves several steps, such as determining the disease condition or target, validating the target, finding a lead, optimizing the lead, conducting preclinical research, toxicity analysis, formulating the drug, conducting clinical trials, obtaining approval, and launching the product with safety or post-marketing surveillance (Hughes et al. 2011). On the other hand, drug repurposing (DR), also known as reprofiling, repositioning, retasking, or therapeutic switching, is a strategy that uses drugs outside of their original medical requirements (Menduti et al. 2020; Kulkarni et al. 2023). It bears the advantages of minimal failure risk, short cycle time, high success rate, and inexpensive investment (Flower 2020).

The repurposed drugs can be directly used for the testing and trial phase saving approximately 6–9 years of formulation and synthesizing time. As a result, it lowers the overall risk, development time, and expense. Without specifically describing the mechanism of action, repurposing can find new compounds based on phenotypic improvements. These compounds can then be directly examined in preclinical animal models, with the results being more relevant to clinical applications and research and the phase II clinical trials could be the next step in the process (Kulkarni et al. 2023). Therefore, repurposed medications carry little risk of failure. Navigating regulatory constraints is a major barrier to the development of novel medications. Complete information on quality, safety, and effectiveness is required for drug approval under the strict regulations set by regulatory bodies like the FDA and EMA. The time, money, and experience needed to meet these regulatory requirements are substantial, which adds to the intricacy of the process of developing drugs from scratch (Kulkarni et al. 2023).

Due to this reason, DR has been found to be an effective strategy for orphan diseases, such as SMA. SMN2 promoter activity, SMN2 splicing modulation, and stabilization of SMN2 mRNA or SMN protein are just a few of the probable in vitro activities that have been demonstrated by a number of studies that have effectively repurposed FDA-approved medications for the treatment of SMA (Prieto-Martínez et al. 2019). Sodium butyrate, phenylbutyrate, and valproic acid (VPA) are a few examples of histone deacetylase (HDAC) inhibitors that have been studied in the context of SMN2 promoter activity thus far (Chong et al. 2021). They have shown that both in animal models and in cells produced by patients, the levels of SMN protein have increased. Gene expression is activated through the modification of chromatin structure by HDAC, which results in a transcriptionally repressed area of chromatin that is tightly wound. According to a recent study, the combined action of nusinersen and HDAC has increased the expression of FL-SMN protein, which is generated from SMN2 (Pagliarini et al. 2020). As a result, the frequency of nusinersen medication might be decreased, which would lessen the financial strain on SMA patients.

Konieczny et al. discovered a repurposed small molecule called moxifloxacin which is an antibiotic with the potential to become a new medication for SMA (Konieczny and Artero 2020). They utilized the Prestwick Chemical Library drug database which consists of almost 1280 compounds (Pushpakom et al. 2019; Konieczny and Artero 2020; Lipinski and Reaume 2020). The area of SMA has also utilized in-vivo phenotypic screenings, which have made it possible to identify small compounds that precisely target RNA splicing, increasing the quantities of SMN protein and the exon seven inclusion of the SMN2 transcript. The initial report of a phenotypic screen yielding selective SMN2 splice modulators was published by Naryshkin et al. in 2014 and led to the discovery of risdiplam which is approved for adults and children two months and older as a treatment for SMA (Naryshkin, et al. 2014). The splicing modulator Branaplam (LMI070) was then discovered by Palacino et al. (2015). In addition to that, the novel SMN-independent targets and drug paradigms like olesoxime, were discovered by DR phenotypic screening. Since this compound can prevent MNs from degenerating and can maintain mitochondrial activity, it has been suggested as a possible treatment for not only SMA but also Amyotrophic lateral sclerosis (ALS) (Chong et al. 2021). Finding medications that are presently used to treat other neuromuscular illnesses may prove to be a beneficial repositioning strategy in the treatment of SMA. FDA approved medications that modify the pathogenetic pathways that both illnesses share, such as riluzole, which is frequently used to treat ALS, have been suggested for SMA patients (Calder et al. 2016; Chong et al. 2021). Rasalgiline and masitinib, two other medications that were initially developed to treat various neurodegenerative illnesses, could turn out to be an effective therapy for SMA (Hoolachan et al. 2019). A variety of cell-based assays are typically used in in-vitro phenotypic screenings, these include highly engineered immortalized cell lines, cellular disease models, and various types of induced pluripotent stem cells (iPSCs). Additionally, whole-organism phenotypic assays (using models of C. elegans, drosophila, zebrafish, and mice) are also crucial due to their physiological relevance (Menduti et al. 2020).

Repurposed Drugs Under Clinical Trials

Riluzole

Riluzole is a member of benzothiazole class and was originally used in treating amyotrophic lateral sclerosis and is tried as a repurposed drug in SMA. The multicentric, randomized, double-blind ASIRI trial was launched to assess the effectiveness and tolerability of the drug riluzole in children and young people of ages 6 – 20 years diagnosed with types 2 and 3 SMA (NCT00774423). This trial planned to observe whether the disease can be stabilized and progression of paralysis can be stopped. Additionally, a proposal was made to conduct an open-label trial following the ASIRI study to assess long-term safety effects. However, as of now, reported outcomes of the ASIRI study have not been observed.

Olesoxime

Olesoxime belongs to the cholesterol-oxime family and is used for several neurodegenerative diseases. Clinical trial NCT02628743, also known as OLEOS, is a continuation of an earlier trial NCT01302600 and evaluated the long-term safety and efficacy of olesoxime in SMA patients. It reported patients treated with olesoxime; motor function had non-significant changes in motor function over a period of one year but declined after that. The decline was faster for younger patients of age less than 15 years and also for type 2 patients (Muntoni et al. 2020).

Another study was conducted to evaluate the efficacy and safety of olesoxime in non-ambulant type 2 and type 3 patients aged 3–25 years (NCT01302600). This multicenter, double-blind, randomized, adaptive, parallel-group, placebo-controlled 3-stage study was conducted on 198 patients among them 165 patients received olesoxime and rest were treated as placebo. Over the 24 months trial duration, patients who took olesoxime maintained motor functions. However, side effects like pyrexia, vomiting, cough, and nasopharyngitis were observed (Bertini et al. 2017). Initial clinical data suggested that benefits from olesoxime, however the overall efficacy and effectiveness were insufficient. Another study showed after 18 months of treatment, the motor neuron function worsened in numerous patients raising concern on its viability. Hence, it is not pursued as a treatment option.

Myostatin Inhibitors

Myostatin released by skeletal myocytes is a negative regulator of skeletal muscle development. Its inhibition improves muscle growth and prevent or mitigate muscular atrophy and hence considered as a viable target for SMA. Early research in mice showed that follistatin, a naturally occurring inhibitor of myostatin, blocked myostatin to enhance muscle growth, mobility, and longevity. However, there was no noticeable gain in muscle growth or survival in mice when myostatin was genetically removed or when follistatin levels were raised. ActRIIB-Fc, another inhibitor, only slightly improved mobility. Possible causes of these inconsistent results include the severity of the used mouse model (Abati et al. 2022).

In the milder SMA model, muscle weight rose but no survival benefit was observed when myostatin inhibition was tested. It indicates the requirement for SMN-upregulating compounds. In mice, myostatin inhibition combined with SMN-boosting medications resulted in greater muscle mass, better motor performance, and increased survival. Additionally, SRK-015P, a specific antibody that targets myostatin, improved muscle mass and slowed muscle loss. Clinical trials for SMA are presently testing the improved version, SRK-015 also known as apitegromab. The safety, pharmacokinetics, pharmacodynamics, and lack of immunogenicity of apitegromab were validated in a phase 1, double-blind, placebo-controlled research conducted on healthy adults. Single or multiple intravenous doses of 1, 3, 10, 20 and up to 30 mg/kg were administered to the participants; the doses were well tolerated and did not cause the development of anti-drug antibodies. The phase 2 TOPAZ trial (NCT03921528), which aims to evaluate apitegromab in patients with SMA type 2 and type 3, was made possible by these encouraging outcomes. RO7204239 (GYM329), another myostatin inhibitor is also under clinical trial (Abati et al. 2022).

Other Drugs

There are few other drugs which are repurposed for SMA and under clinical trials.

The anticonvulsant medication, gabapentin which is typically used for the management of seizures was tested on type 2 and 3 SMA patients based on its effect on Amyotrophic Lateral Sclerosis (ALS) patients. It works by targeting the excitotoxicity however, one study showed some positive effect on arm and knee movement (Merlini et al. 2003) but no effect was observed in the other study (Miller et al. 2001).

Reldesemtiv, a skeletal muscle troponin activator was tested on SMA patients of types 2, 3, and 4 (NCT02644668). The results of the phase II study were not really promising as out of 10 primary outcomes only improvement of expiratory pressure was observed.

Somatotropin is typically used as replacement therapy in several conditions of growth failure, and weakness in children and adults. It was tested on SMA patients of type 2 and type 3 patients (NCT00533221) but it did not deliver promising results in the improvement of muscle function (Kirschner et al. 2014).

Pyridostigmine is a cholinesterase inhibitor that is typically used to treat the symptoms of myasthenia gravis and congenital myasthenic syndromes. This drug was tested on SMA patients of types 2, 3 and 4 (NCT02941328) (Stam 2018). The results show reduction in fatigability and improved endurance test suggesting usage of pyridostigmine as an additional drug (Stam 2022).

4-Aminopyridine also known as dalfampridine is a potassium channel blocker is used to help multiple sclerosis patients walk. It is being tested on type 3 SMA patients (NCT01645787) but the outcome is not reported.

Amifampridine is typically used to treat Lambert-Eaton myasthenic syndrome. It was tested on type 3 SMA patients. The phase 2 trial (NCT03781479) of this drug in ambulatory type 3 patients highlighted that there was a significant improvement in the motor neuron function of the patients with no signs of serious adverse effects (Bonanno et al. 2022).

Salbutamol, a β2-adrenoreceptor agonist originally licensed for asthma, have shown potential in several studies for type 2 and 3 patients (Pane et al. 2008; Khirani et al. 2017; Frongia et al. 2019; Feng et al. 2023).

Repurposed Drugs Under Pre-clinical Studies

Histone Deacetylase (HDAC) Inhibitors

The inhibitors of histone deacetylase (HDAC) promote gene transcription and is widely studied as potential drug of SMA (Mohseni et al. 2013).

Vorinostat

Vorinostat is an inhibitor of HDAC, which structurally belongs to hydroxymate group (Athira et al. 2021). It has demonstrated potential as a safe, effective option for treating patients with SMA. VOR increases the levels of SMN in several neuroectodermal tissues by up-regulating the SMN2 gene. By disrupting the DNA methylation process, it aids in addressing the issue of the long transcript of SMN2 gene (LT-SMN2) suppression in SMA fibroblasts. It reverses the effects of DNA methylation, maintaining the LT-SMN2 gene’s activity and enabling it to generate the required protein, which aids in mitigating the molecular dysfunction associated with SMA. In severe SMA mice models, VOR therapy prolongs life span, increases the size of muscle fibers and neuromuscular junctions, raises the amounts of SMN RNA and protein, and decreases motor neuron degeneration (Athira et al. 2021).

Sodium Butyrate

Sodium butyrate (BA) enhances the generation of the exon 7-containing SMN protein from the SMN2 gene. This is accomplished by changing the RNA splicing pattern, which produces an SMN2 transcription profile. In order to further increase the therapeutic efficacy and pharmacokinetic features and provide better clinical outcomes, BA-derivatives such as VX563, have been created (Butchbach et al. 2016).

Phenylbutyrate

Phenylbutyrate which has been recognized for its function as a histone deacetylase inhibitor, has shown to upregulate the expression of SMN transcripts in fibroblast cells and leukocytes from patients suffering from SMA. However, clinical trials testing oral phenylbutyrate in 107 persons over treatment periods ranging from three to 24 months did not produce statistically significant improvements in motor function for patients with SMA types 2/3. This demonstrates the difficulties in converting laboratory results into efficient SMA therapy (Calder et al. 2016; Wadman 2020).

Valporic Acid (VPA)

Numerous research looked into valproic acid (VPA) as a possible treatment for SMA. The initial optimism of VPA stemmed from its potential to increase SMN2 gene expression by inhibiting histone deacetylase. However, there have been conflicting therapeutic benefits in motor function despite elevated SMN transcripts with VPA as shown by several open-label trials and case series. A prospective investigation in children with SMA type 3 found no significant gains in motor function, whereas a retrospective case series revealed a range of outcomes in motor abilities. The evidence at hand indicates that VPA has limited efficacy when used as a stand-alone treatment for SMA, emphasizing the need for additional thorough controlled trials to confirm its potential as a treatment (Butchbach et al. 2016; Elshafay et al. 2019).

Moxifloxacin

The synthetic fluoroquinolone antibiotic moxifloxacin modifies the splicing of many genes, including SMN2, by blocking the activity of the enzyme topoisomerase II (Konieczny and Artero 2020). The inclusion of SMN2 exon 7 is promoted by moxifloxacin, which results in a dose-dependent rise in SMN protein levels. HeLa cells treated with moxifloxacin saw about twice as many Cajal bodies as before, which is in line with the observation that Cajal body numbers increased following SMN overexpression in HeLa cells (Servais et al. 2021). Higher amounts of SMN protein were thought to be the cause of the increased Cajal body sizes and numbers, which were attributed to an increase in snRNP abundance. The expression levels of several splicing factors are changed by moxifloxacin therapy. For this reason, it is anticipated that this substance will affect not just SMN2 pre-mRNA splicing but also that of other transcripts (Servais et al. 2021).

Harmine

Harmine stands out as a promising drug for potential SMA treatment. Detailed examination of harmine’s impact on cellular and animal models of SMA has revealed its capability to alleviate a range of disease symptoms across molecular, behavioral, and histological dimensions (Meijboom 2021). Snrnp27, a gene involved in pre-mRNA splicing that is downregulated in SMA muscle relative to healthy animals, was significantly upregulated in response to harmine treatment. SMA mice and their healthy littermates showed similar changes in Snrnp27 levels, despite the fact that these changes were minor. This shows that harmine may have a positive and direct effect on Snrnp27 expression. Harmine also has proven neuroprotective qualities, such as upregulating GLT-1 expression in a variety of neurodegenerative models, and can cross the blood–brain barrier, which adds to its therapeutic potential. In addition to that, the research showed that harmine administration significantly increased GLT-1 expression in the spinal cord of SMA mice, which may have mitigated the decreased glutamate transporter activity seen in SMA patients (Meijboom 2021). Moreover, harmine administration resulted in a significant increase in the number of motor neurons in the spinal cord of SMA mice, suggesting that it may have neuroprotective benefits and prompting further investigation into its therapeutic potential for the management of SMA (Meijboom 2021).

Prednisolone

Prednisolone belongs to the group of drugs known as corticosteroids. It alters the function of the immune system and reduces swelling and redness. Prednisolone has been shown in earlier studies to have important beneficial impacts on SMA rats, resulting in improvements to weight, muscle health, and survival (Hoolachan 2024). In order to investigate its molecular effects on SMA skeletal muscle, a thorough investigation used bulk RNA-sequencing (RNA-Seq) on triceps muscle tissue from SMA mice that were not treated and mice that were treated with prednisolone, as well as healthy littermates (Hoolachan 2024). In SMA mice, prednisolone therapy raised the expression of many genes back to levels similar to those in healthy mice. Prednisolone has been shown to influence important biochemical pathways related to skeletal muscle functions, including metabolism, atrophy, and regulatory function (Hoolachan 2024). Interestingly, there is a strong correlation between these pathways and pathways connected to SMA, indicating the potential of prednisolone to mitigate muscular diseases. The results demonstrate how prednisolone can reduce SMA-related muscle diseases by focusing on important muscle metabolic and regulatory networks (Hoolachan 2024). The therapeutic potential of prednisolone in the treatment of SMA is illuminated by this thorough understanding of its molecular effects.

Conclusions

Being a genetically inherited neurodegenerative disease, genetic therapies have stand out for providing novel opportunities for precise intervention and disease transformation. FDA-approved medications nusinersen, ridiplasm, and AVXS-101 are currently being used in the treatment of SMA. Treatment efficacy depends on the patient’s age and SMA type. Early diagnosis is also beneficial. Interventions aimed at repairing MNs seem to be particularly effective in the initial phases of SMA disorder, when the MNs are still alive and the muscles still work. However, the available treatments have significant drawbacks which is why drug repurposing is being explored as it is less risky and saves time and money.

Several drugs have been proposed to treat SMA, possibly affording a wide variety of potential treatments. Prominent candidates among them are branaplam, riluzole, olesoxime, moxifloxacin, vorinostat, harmine, and prednisolone. Riluzole, and olesoxime have undergone clinical trials and could emerge as a potential therapeutic efficacy in human patients. Animal models have been used to investigate vorinostat and harmine, providing important information about their pharmacological effects and possible applicability for additional research in human trials. Several other drugs like edaravone, ACE-031, bimagrumab, tirasemtiv, recombinant IGF-1 (mecasermin) which are being trialed for different neurological disorders are also considered as promising re-purposed drug for SMA (Chaytow et al. 2021). This range of drug repositioning initiatives emphasizes the comprehensive strategy used to treat SMA and the continuous search for efficient treatments using already-approved drugs.

Overall, we observe, that even with significant attempts, not only the current treatment options but also drugs under clinical and pre-clinical studies are limited. It demands more methodical approach on molecular basis to find new drugs where repurposed drugs are potential candidates. We can expedite the development of essential therapeutic approaches for SMA by optimizing the process of drug repurposing through the systematic identification of off-target or new target effects of the approved drugs.

Author Contributions

All authors contributed to the study conception and design. The first draft of the manuscript was written by S.B. and N.B. The manuscript was further reviewed and edited by N.B., J. G. and S.A. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical Approval

This study does not require any ethics approval.

Informed Consent

Not applicable.