INTRODUCTION:

Spinal muscular atrophy (SMA) is a group of neuromuscular disorders characterized by the degeneration and dysfunction of motor neurons in the spinal cord due to mutations in the SMN1 gene, leading to progressive muscle atrophy, weakness, and paralysis. The disease was first described in the 1890s by Werdnig and Hoffmann^1,2. SMA is classified into clinical groups based on the age at onset and the maximum motor milestones achieved³.

It is one of the most common autosomal recessive diseases and a leading cause of mortality in childhood, with a global incidence of approximately 1 in 12,000 and an overall carrier frequency of 1 in 54, varying from 1 in 54 among white and Asian populations to 1 in 100 among African populations⁴. Approximately 95% of individuals with SMA have a homozygous deletion of the survival motor neuron 1 (SMN1) gene⁵. The clinical variability in SMA is mainly attributable to the variable copy number of SMN2, a gene paralogous to SMN1 that produces a protein lacking exon 7 (SMNΔ7) due to alternative splicing⁶. This paper reports on current therapies and multidisciplinary approaches, including pulmonary care, GI care, nutritional supplements, and orthopedic management. Recently, antisense oligonucleotide (ASO) therapy with nusinersen and gene therapy with onasemnogene abeparvovec have become available for SMA patients⁷. These effective treatments have introduced medical and financial challenges that the SMA community must address.

VARIOUS CATEGORY OF SMA:

SMA is categorized into different types based on the age of onset (Table 1) and the maximum motor function achieved. These categories help in understanding the range of clinical presentations and prognosis associated with SMA, guiding treatment and care strategies tailored to the specific needs of individuals.The main types of SMA are:

SMA Type-1: Very weak infants unable to sit unsupported (Most severe and common form of the diseases):

Individuals with SMA type 1 exhibit weakness within the first six months of infancy and never achieve the ability to sit independently. This form of SMA is often associated with death or the need for permanent ventilation. Patients develop hypotonia, symmetrical flaccid paralysis, and lack head control. Some children may also present with congenital bone fractures and extremely thin ribs^8-10. The clinical diagnosis of SMA type 1 includes indicators of severity: a) Severe weakness from birth or the neonatal period, with no head control ever achieved. b) Weakness appearing shortly after the neonatal period, generally within two months, with no head control ever achieved. c) Weakness after the neonatal period, with some head control possibly achieved, and in some cases, the ability to sit with support¹¹. Clinically, all children with SMA type 1 develop trunk and limb weakness, which extends to the intercostal muscles, disrupting normal respiratory function. The risk of early mortality is closely linked to bulbar dysfunction and respiratory complications¹². Historically, children with SMA type 1 have had a life expectancy of less than two years. However, recent clinical trials have significantly improved survival rates¹³.

SMAType-2: The non-ambulant patients able to sit independently

SMA Type 2 is characterized by onset between 6 to 18 months of age. Patients with this type can sit unsupported, and some of the better-developed individuals may acquire the ability to stand but are unable to walk independently. Additionally, patients may experience difficulties with swallowing, as well as problems with coughing and clearing secretions from the trachea. Life expectancy for individuals with SMA Type 2 varies, typically ranging from 10 to 40 years^{12, 14}.

SMA Type-3: Up to ambulant patients with childhood:

Also known as Juvenile SMA or Kugelberg-Welander syndrome, SMA Type 3 has an onset after 18 months of age. Patients with this type are able to walk independently. During childhood, some patients may require wheelchair assistance due to proximal muscle weakness. Those with a later onset of symptoms are often able to walk throughout their lives¹⁵. Although they remain ambulant during childhood, they may lose this ability as they age. Swallowing and coughing problems are less common in SMA Type 3 patients compared to those with Type 2.

SMAType-4: Adult Onset SMA:

SMA type 4, also known as adult-onset SMA, typically begins in adulthood, usually after the age of 30. However, Russman reports that it can emerge after 10 years of age, while Wang states that weakness typically appears from 30 years of age^{12, 14}. Patients experience mild to moderate muscle weakness that progresses slowly over time. The weakness primarily affects the proximal muscles, but individuals often retain the ability to walk for many years. Swallowing and respiratory problems are less common compared to the earlier-onset types. Life expectancy is generally normal, although gradual loss of motor function can lead to significant disability. This group includes patients who are able to walk into adulthood without significant respiratory and nutritional problems¹⁶.

Table 1: Clinical classification criteria for SMA

Category	Age of onset	Highest functions	SMN 2 copy number	Natural age of death
Type 1 (severe)	0-6 months	Never sit or walks	In 80% patients 1 or 2 copies	Life expectancy < 2 years if untreated
Type 2 (intermediate)	7-18 months	Sit never stands	Greater than 80% patients 3 copies	Survival into adult hood
Type 3 (mild)	> 18 months	Stands and walks during adult hood	Greater than 95% patients 3-4 copies	Survival into adult hood
Type 4 (mild)	2^nd or 3^rd decade	Walks during adult years	4 or > 4 copies	Survival into adult hood

CAUSES OF SMA:

SMA results from a mutation in the SMN1 gene. This gene is responsible for producing the survival motor neuron (SMN) protein, which is essential for maintaining the health and normal function of motor neurons. In patients with SMA, both copies of the SMN1 gene are mutated, leading to a decrease in the production of the SMN protein. Without adequate levels of SMN protein, motor neurons in the spinal cord degenerate and are lost (Figure 1). This degeneration prevents muscles from receiving proper signals from the brain. The key factors contributing to the development of SMA include:

1. SMN1 Gene Mutation:

· Primary Cause: The majority of SMA cases are caused by mutations or deletions in the survival motor neuron 1 (SMN1) gene, located on chromosome 5q13. This gene is responsible for producing the SMN protein, which is critical for the maintenance and function of motor neurons.

· Mechanism: When the SMN1 gene is mutated or deleted, the body produces insufficient amounts of the SMN protein, leading to the degeneration of motor neurons in the spinal cord. This results in the muscle weakness and atrophy characteristic of SMA.

2. SMN2 Gene Copy Number:

· Modifier of Severity: The severity of SMA is largely influenced by the number of copies of the SMN2 gene, a nearly identical gene located near SMN1. While SMN2 also produces the SMN protein, it does so less efficiently due to alternative splicing that excludes exon 7 in the majority of transcripts.

· Impact: Individuals with more copies of the SMN2 gene tend to have a milder form of SMA because they produce a higher amount of functional SMN protein.

3. Inheritance Pattern:

· Autosomal Recessive Disorder: SMA is inherited in an autosomal recessive pattern. This means that an individual must inherit two mutated copies of the SMN1 gene (one from each parent) to develop the disease.

· Carrier Frequency: Approximately 1 in 54 individuals is a carrier of the SMN1 gene mutation. Carriers typically do not show symptoms of the disease but have a 25% chance of having an affected child if both parents are carriers.

4. Rare Genetic Causes:

· Non-SMN Related: Although most cases of SMA are related to SMN1 mutations, there are rare forms of SMA caused by mutations in other genes. These include genes such as UBA1 (associated with X-linked SMA).

· Different Mechanisms: These non-SMN related forms of SMA may involve different pathogenic mechanisms but result in similar clinical features of motor neuron degeneration and muscle atrophy.

Understanding these genetic causes is crucial for diagnosing SMA and developing targeted therapies. Advances in genetic testing and molecular biology have led to improved diagnostic capabilities and the development of treatments that specifically address the underlying genetic defects in SMA.

Figure 1: The degeneration of motor neurons results in a gradual decrease in muscle mass and strength, known as atrophy

Figure 2: Both the genes SMN1 and SMN2 are involved in the production of the survival motor neuron (SMN) protein. SMN1 typically provides humans with the requisite quantity of SMN protein essential for a normal phenotype. However, splicing in exon 7 of SMN2 results in the production of both nonfunctional protein and a limited amount of functional protein

The SMN1 gene is responsible for synthesizing normal levels of the SMN protein. Conversely, the SMN2 gene produces significantly lower levels of SMN protein (Figure 2). Only 10-25% of the proteins produced by SMN2 are functional, while the remaining 75% are unstable and degrade rapidly¹⁷. However, splicing in exon 7 of SMN2 results in the production of both nonfunctional and a small amount of functional SMN protein.

The majority of SMA cases arise from the absence of the SMN1 gene. In approximately 95% of SMA patients, this absence manifests as either a homozygous deletion of SMN1 exon 7 or a gene conversion from SMN1 to SMN2. Rarely, around 5% of cases involve compound heterozygotes who carry both an SMN1 exon 7 deletion and an SMN1 protein mutation (normal: Figure 3A, variants: Figure 3B and C)¹⁸. Other iatrogenic mutations found in the compound heterozygous state with an SMN1 deletion may include missense, nonsense, insertions, duplications, and deletions^19,20.

Figure 3: A-A chromosome that contains normal copies of both the SMN1 and SMN2 genes. B- The empty box represents a deleted SMN1 gene. C- Gene conversion involves a transition from C (centromere) to T(telomere) in SMN1, causing the SMN1 copy to closely resemble SMN2. This altered SMN1 is then considered SMN2-like

SMA DIAGNOSIS:

Diagnosing SMA typically involves a combination of clinical evaluation, genetic testing¹⁶, and specialized tests to assess muscle function. The diagnostic process includes the following steps:

1. Clinical Evaluation:

· Medical History: A thorough review of the patient's medical history, including developmental milestones and family history of neuromuscular disorders.

· Physical Examination: Assessment of muscle strength, tone, reflexes, and motor function. Specific features associated with SMA, such as hypotonia (reduced muscle tone) and muscle atrophy, may be observed.

2. Genetic Testing:

· SMN1 Gene Analysis: Molecular genetic testing to identify mutations or deletions in the SMN1 gene¹⁶. This is typically performed using techniques such as polymerase chain reaction (PCR) or multiplex ligation-dependent probe amplification (MLPA).

· SMN2 Copy Number Analysis: Quantification of the number of SMN2 gene copies to assess disease severity and guide prognosis. This is often determined through genetic sequencing or quantitative PCR.

3. Electrophysiological Studies:

· Electromyography (EMG): Measures the electrical activity of muscles to assess nerve and muscle function. EMG findings in SMA typically include reduced recruitment and abnormal motor unit potentials.

· Nerve Conduction Studies: Assess the speed and strength of electrical impulses traveling along nerves. In SMA, nerve conduction studies may reveal reduced nerve conduction velocities.

4. Muscle Biopsy (Optional):

· Histological Examination: Analysis of muscle tissue under a microscope to assess for characteristic features of SMA, such as muscle fiber size variation and motor neuron loss.

· Immunohistochemistry: Staining techniques to identify specific proteins associated with SMA, such as the survival motor neuron protein.

5. Other Tests:

· Serum Creatine Kinase (CK): Elevated levels of CK may indicate muscle damage but are not specific to SMA.

· Pulmonary Function Tests: Assess respiratory muscle strength and lung function, as respiratory complications are common in SMA.

· Nutritional Assessment: Monitoring nutritional status and swallowing function, as feeding difficulties may arise in severe cases of SMA.

Early diagnosis of SMA is critical for initiating appropriate interventions and supportive care measures to optimize outcomes and improve quality of life for affected individuals.

MANAGEMENT:

Multi-disciplinary approach for Management:

A multi-disciplinary approach (Figure 4) plays a pivotal role in the management of SMA patients²¹. The physician, particularly a neurologist or pediatric neurologist knowledgeable about the disease, will oversee the coordination of care for the patient, facilitating ongoing monitoring of disease progression.

Figure 4: Multi-disciplinary approaches for the management of SMA patient

Pulmonary care:

Pulmonary complications are a significant source of morbidity and mortality in SMA¹². These complications encompass a range of issues, including weak coughing and ineffective clearance of lower airway secretions. In SMA type 1, all children experience respiratory insufficiency or failure due to muscular weakness, which limits their ability to move and cough effectively. Consequently, they are prone to infections, which can lead to atelectasis and pulmonary collapse²². Specialized clinical interventions and respiratory support, ranging from noninvasive ventilation to tracheostomy and mechanical ventilation, are crucial for this subgroup of SMA patients. These interventions help clear the airways and facilitate secretion movement. Airway clearance techniques (ACTs) provide effective solutions for clearing secretions from the lungs. There are three major categories of techniques that can help improve pulmonary complications in SMA (Table 2):

1. Cough augmentation techniques: These techniques focus on enhancing cough effectiveness for clearing secretions from the central and upper airways.

2. Secretion mobilization techniques: These techniques facilitate the clearance of secretions from the peripheral airways, aiding in their removal from the lungs.

3. Protection of airways: This involves strategies aimed at safeguarding the airways to prevent aspiration and other respiratory complications.

Implementing these techniques can significantly alleviate pulmonary issues and improve respiratory function in individuals with SMA⁴².

Gastrointestinal (GI) care and Nutritional supplement:

Patients with SMA commonly experience GI issues, including gastroesophageal reflux, abdominal distension, constipation, and delayed gastric emptying¹². These complications can contribute to generalized weakness and difficulties in feeding and swallowing due to bulbar dysfunction, tongue weakness, and impaired mouth opening. Gastroesophageal reflux, in particular, poses a significant risk of morbidity and mortality due to its association with silent aspiration, which can lead to aspiration pneumonia¹².

To manage gastroesophageal reflux, patients may be prescribed gastric acid neutralizers or inhibitors, such as proton pump inhibitors and H2 blockers. Additionally, modifying food consistency can help mitigate aspiration risk associated with feeding and swallowing difficulties. Transitioning to a semisolid diet and using thickened liquids can compensate for poor chewing ability. Malnutrition is prevalent, especially in SMA type 1 and severe type 2 patients. Therefore, consulting with a nutritionist is beneficial. In severe cases where children are unable to feed orally, parental supplementation is necessary to prevent muscle catabolism¹².

Orthopedic management:

For non-sitters with SMA, specific rigid braces can aid in achieving a stable sitting position. Spinal bracing may also be used to delay the onset of progressive scoliosis resulting from muscle weakness. However, caution must be exercised when applying spinal bracing to patients with SMA type 1 or type 2, as it can significantly reduce expiratory tidal volume while in the sitting position. Therefore, its use should be carefully considered²³.

Scoliosis is uncommon before early childhood and is typically not observed in children with type 1 SMA. However, it is prevalent in those with type 2 SMA and less so in those with type 3 SMA²⁴. Interventions aimed at mitigating the adverse effects of scoliosis include pain management, postural control, adapting daily activities, and facilitating mobility with the use of wheelchairs¹². Gondard et al. demonstrated the advantages of regular exercise in mutant rats with type 2 SMA and observed positive outcomes²⁵. Their study revealed that mutant rats subjected to force running in a wheel experienced a significant increase in survival time compared to non-exercised rats. Additionally, the researchers noted a reduction in medullary motor neuron death. These findings suggest that engaging in regular physical exercise may offer protective benefits against disease progression in SMA.

Physiotherapy:

Physiotherapy plays a crucial role in the management of SMA by focusing on maintaining or improving muscle strength, mobility, and overall functional abilities. The goals of physiotherapy in SMA include:

1. Muscle Strengthening: Physiotherapy aims to preserve existing muscle strength and improve muscle function through targeted exercises and resistance training.

2. Range of Motion Exercises: Stretching and range of motion exercises help prevent contractures and maintain flexibility in the joints, thereby enhancing mobility and preventing deformities.

3. Postural Management: Physiotherapists work with individuals with SMA to optimize their posture, positioning, and alignment to reduce the risk of developing orthopedic complications such as scoliosis and kyphosis.

4. Mobility Training: Physiotherapy interventions focus on maximizing independence in mobility, whether through walking, standing, or using assistive devices such as wheelchairs or walkers.

5. Breathing Exercises: Respiratory physiotherapy techniques, including deep breathing exercises and assisted coughing, help maintain lung function and prevent respiratory complications such as pneumonia.

6. Assistive Devices and Equipment: Physiotherapists assess the individual's needs for assistive devices and recommend appropriate mobility aids, orthoses, or adaptive equipment to facilitate independence and safety in daily activities.

7. Education and Support: Physiotherapists provide education and support to individuals with SMA and their caregivers on proper positioning, transfers, and techniques to optimize function and prevent secondary complications.

Overall, physiotherapy plays a vital role in the holistic management of SMA, promoting physical function, independence, and quality of life for individuals living with the condition.

Pharmacological therapeutic strategies for SMA:

The pharmacological treatment for SMA includes the modulation of SMN2s plicing, stabilizing SMN protein, development of neuroprotective compounds, muscle enhancing therapies and gene therapy.

Modulation of SMN 2 splicing:

In the majority of SMA patients, the production of truncated SMN protein is attributed to the splicing of exon 7 in the SMN2 gene transcription. Strategies to prevent this exon exclusion can lead to an increase in full-length SMN protein. Sodium Vanadate, a phosphatase inhibitor, has shown the ability to stimulate exon 7 inclusion into transcripts derived from the endogenous SMN2 gene²⁶. Similarly, Idarubicin, a chemotherapeutic agent, has been observed to significantly elevate full-length SMN protein levels in SMA type 1 patients by promoting exon 7 inclusion in SMN2 gene transcripts. However, due to its side effects and known toxicity profile, Idarubicin may not be suitable for treating young SMA patients. Risdiplam, also known as RO703406, is a molecule that modulates SMN2 gene splicing by binding to two sites in SMN2 pre-mRNA: the 5ʹ splice site of intron 7 and exonic splicing enhancer 2 in exon 7, thereby increasing levels of full-length SMN mRNA and protein²⁷.

Nusinersen, marketed as Spinraza, is a modified ASO that binds to a specific sequence in the intron downstream of exon 7 of SMN2 mRNA transcripts, promoting the production of full-length SMN protein. Approved by the US FDA (United States Food and Drug Administration) in December 2016 for the treatment of children and adults with SMA, Nusinersen is administered intrathecally with the goal of increasing SMN protein production²⁸. In this therapy, nucleotides bind to the mRNA sequence of SMN2, altering the splicing process to include exon 7 instead of excluding it, thereby enhancing the production of functional SMN protein.

Albuterol (salbutamol), a beta-2-adrenoceptor agonist, has been found to increase SMN2 full-length mRNA and SMN protein levels in fibroblast cells derived from SMA patients²⁹.

Muscle enhancing therapy:

Reldesemtive (CK-2127107) is under development to enhance skeletal muscle function during fatigue. Acting as a selective troponin activator, it boosts the affinity of troponin C to calcium, thereby triggering muscle contraction³⁰. Following the confirmation of its safety in phase II trials, its efficacy was evaluated in a double-blind, randomized, placebo-controlled trial involving 70 patients with SMA types 2 to 4. The trial investigated the effects of oral administration at two different doses: 150mg and 450mg twice daily. Results indicated that the higher dose group showed a trend towards improvement from baseline in the six-minute walk test (6MWT) and maximal expiratory pressure (MEP). Adverse events were comparable between the treated and placebo groups³¹.

Stabilizer of SMN protein:

A stabilizer of SMN protein is a substance or compound that enhances the stability and longevity of the SMN protein within motor neurons. These stabilizers work to prevent the degradation or breakdown of the SMN protein, thereby increasing its presence and functionality within cells. Stabilizing the SMN protein is of significant interest in the treatment of SMA, as insufficient levels of SMN protein are characteristic of the disease. By enhancing the stability of SMN protein, stabilizers may help mitigate the progression of SMA and improve motor function in affected individuals.

Indoprofen has demonstrated the ability to increase SMN protein levels by 13% in treated fibroblast cells and reduce embryonic lethality in SMA mutant mice³². These findings suggest that indoprofen may have a stabilizing effect on the SMN protein, which could be beneficial in the management of SMA. Further research is needed to fully elucidate the mechanism of action and potential clinical utility of indoprofen in SMA treatment. Likewise, the aminoglycoside gentamicin has been identified as an agent capable of suppressing termination at the target D7-SMN stop codon. Injection of gentamicin intraperitoneally in SMN ∆7 mice led to an increase in SMN protein levels, as measured in the brain, kidney, and spinal cord³³. Additionally, it has been found to decrease embryonic lethality in SMA mutant mice.

Neuroprotective:

Neuroprotective refers to the ability of a substance or intervention to protect neurons from damage, degeneration, or death. In the context of SMA, neuroprotective strategies aim to preserve the health and function of motor neurons, which are progressively lost in the disease. These approaches may involve the use of pharmacological agents, gene therapies, or other interventions that target the underlying mechanisms of neuronal degeneration in SMA. By promoting neuronal survival and reducing the progression of motor neuron loss, neuroprotective strategies have the potential to slow disease progression and improve outcomes for individuals with SMA.

Protecting SMN-deficient motor neurons from degeneration is a critical aspect of managing SMA. Riluzole is a compound known for its neuroprotective effects. In SMA, insufficient elimination of glutamate after presynaptic depolarization can result in increased levels of free radicals, leading to motor neuron degeneration. Riluzole acts by modulating glutamate release, thereby reducing the accumulation of free radicals and mitigating motor neuron degeneration³⁴.Clinical studies have shown that treatment with riluzole in type 1 SMA patients may prolong survival. By preserving motor neuron function and preventing their degeneration, riluzole offers promise as a therapeutic intervention in SMA management³⁵.

Gene therapy for SMA:

Gene therapy for SMA involves the delivery of functional copies of the SMN1 gene to affected cells in order to compensate for the genetic deficiency causing the disease. This approach aims to increase levels of the SMN protein, which is essential for the health and function of motor neurons.

There are several strategies for delivering SMN1 gene therapy, including:

1. Viral Vector Delivery: Viral vectors, such as adeno-associated viruses (AAVs) or lentiviruses, are used to deliver the SMN1 gene to target cells. These viruses are modified to carry the SMN1 gene and are administered either systemically or directly into the central nervous system (CNS).

2. Exon Skipping: Some gene therapy approaches aim to correct SMN2 splicing defects by skipping exon 7, which results in the production of more functional SMN protein. This can be achieved using ASO or other molecular tools.

3. Gene Editing: Emerging technologies like CRISPR-Cas9 enable precise editing of the SMN1 gene to correct genetic mutations associated with SMA. This approach holds promise for providing long-term correction of the underlying genetic defect.

Several gene therapy products targeting SMA have been developed and evaluated in clinical trials, with some receiving regulatory approval for clinical use. Notably, onasemnogene abeparvovec (Zolgensma) and risdiplam (Evrysdi) are two gene therapy products that have been approved by regulatory agencies for the treatment of SMA.Gene therapy represents a direct and promising approach to treating SMA by replacing the missing SMN1 gene. Initially, gene therapy studies for SMA were conducted in mice, involving intramuscular injections of adenoviral vectors expressing cardiotrophin-1. These deliveries to SMA mutant mice resulted in the protection of both proximal and distal motor neurons³⁶.

Zolgensma, formerly known as AVXS-101, is a gene therapy based on an adeno-associated virus vector that contains the human SMN gene under the control of the chicken beta-actin promoter. Zolgensma addresses the genetic cause of SMA by providing a functional copy of the human SMN gene³⁷. It increases functional SMN protein levels in motor neurons, preventing neuronal cell death and disease progression. Zolgensma is indicated for the treatment of pediatric patients less than 2 years of age with SMA who have bi-allelic mutations in the SMN1 gene. Similarly, self-complementary adeno-associated virus (scAAV) vectors 8 and 9 have been utilized in animal models of SMA to carry SMN1 cDNA. Clinical trial studies have demonstrated increased lifespan in treated patients compared to untreated individuals. However, there are challenges that need to be addressed before gene therapy can become a widespread clinical management option for SMA^38-40.

Gene therapy holds significant promise for the treatment of SMA by addressing the root cause of the disease and restoring SMN protein levels. Ongoing research continues to refine gene therapy approaches and improve outcomes for individuals affected by SMA.

Challenges for SMA therapy:

Current treatment challenges for SMA include:

1. Access to Treatment: Despite the availability of effective therapies such as gene therapy and ASO drugs, access to these treatments may be limited due to factors such as cost, reimbursement issues, and healthcare infrastructure.

2. Early Diagnosis and Screening: SMA can be difficult to diagnose, particularly in milder forms or in regions with limited access to genetic testing. Improving early diagnosis and implementing newborn screening programs can help ensure timely initiation of treatment.

3. Optimizing Treatment Response: While treatments such as nusinersen and onasemnogene abeparvovec have shown efficacy in improving motor function and survival in SMA patients, there is variability in treatment response among individuals. Understanding factors that influence treatment response and optimizing treatment protocols are ongoing challenges.

4. Managing Disease Progression: Current treatments primarily target the underlying genetic defect or increase production of the SMN protein, but they do not address other aspects of disease pathophysiology, such as muscle weakness, respiratory insufficiency, and skeletal deformities. Developing adjunctive therapies to manage disease progression and improve quality of life remains a challenge.

5. Long-term Safety and Efficacy: Long-term data on the safety and efficacy of SMA treatments are still limited, particularly for newer therapies such as gene therapy. Continued monitoring and research are needed to assess long-term outcomes and potential side effects of SMA treatments.

6. Multidisciplinary Care: SMA requires comprehensive multidisciplinary care involving various healthcare professionals such as neurologists, pulmonologists, orthopedic surgeons, physical therapists, and nutritionists. Ensuring access to coordinated multidisciplinary care can be challenging, particularly in regions with limited healthcare resources.

7. Cost and Healthcare Resource Allocation: SMA treatments can be costly, placing a financial burden on healthcare systems and families. Balancing the cost-effectiveness of treatments with equitable access to care is a significant challenge for healthcare policymakers and providers.

Addressing these challenges requires collaboration among healthcare professionals, researchers, policymakers, advocacy groups, and industry stakeholders to improve access to treatment, optimize treatment protocols, and enhance long-term care and support for individuals with SMA.

CONCLUSION:

The current treatment landscape for SMA has witnessed significant advancements, yet several challenges persist. One of the major breakthroughs in SMA treatment is gene replacement therapy, such as Zolgensma (formerly AVXS-101 or Onasemnogene abeparvovec), which utilizes adeno-associated virus vectors to deliver functional copies of the SMN1 gene to affected cells. This therapy has shown remarkable efficacy in infants, but challenges remain regarding its accessibility and affordability. Another approved treatment for SMA is risdiplam (Evrysdi), a small molecule splicing modifier that enhances the production of functional SMN protein by targeting SMN2, the SMN1 paralog that produces low levels of functional protein. Despite its oral administration and broader applicability across SMA types and ages, challenges include the need for long-term data and potential side effects.

The foundation of SMA treatment remains supportive care, which encompasses multidisciplinary approaches. Notably, the survival rate of SMA type-1 has seen a significant increase in recent years. The establishment of the International Standard of Care Committee for SMA in 2005 marked a pivotal step, focusing on key care areas including GI/nutrition, diagnostic, pulmonary, orthopedic/rehabilitation, and palliative care⁴¹. Over the past two decades, the advent of gene therapy has introduced several promising targets for SMA treatment, albeit with considerable costs. Further research is imperative to elucidate the safety and efficacy of these therapies, either alone or in combination. However, the pursuit of a satisfactory drug for SMA treatment remains ongoing.

Additionally, attention must be directed towards addressing the needs of the aging population, including adults with SMA. This necessitates ongoing collaborative efforts among clinicians, scientists, and advocacy groups to advance clinical and therapeutic outcomes for the benefit of SMA patients. Continued dedication to research and innovation is essential to enhance the quality of life and prognosis for individuals affected by SMA.

CONFLICTS OF INTEREST:

The Authors declare that there is no known competing financial interest to write this paper.

ACKNOWLEDGEMENT:

I express my gratitude to Chairperson, Mrs. Anima Dash, College of Pharmaceutical Sciences, Puri, for their encouragement and support in motivating me to write this paper.

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Received on 26.06.2023 Modified on 06.02.2024

Research J. Pharm. and Tech 2024; 17(8):3730-3738.

DOI: 10.52711/0974-360X.2024.00580

		Patient age in years
Techniques	Description	0-2	2-5	> 5
Cough augmentation	Mechanical insufflation-exsufflation Manual assisted cough Inspiratory aids (Intermittent positive pressure breathing, Non-invasive ventilation, Air- stacking	++ + ++	+++ ++ ++	+++ ++ +++
Secretion mobilization	Intrapulmonary percussive ventilation Chest oscillations Assisted autogenic drainage	++ + +	++ + +	++ ++ +
Protection of air ways	Oral suction	+++	+++	++

Nikunja Kishor Mishra1*, Amiyakanta Mishra2, Pravat Kumar Sahoo3, Rosy Priyadarshini2