Spinal Muscular Atrophy (SMA) is a rare genetic disorder that causes progressive muscle weakness and loss of motor function, affecting thousands of individuals worldwide. Characterized by the degeneration of motor neurons in the spinal cord, SMA impacts essential movements such as breathing, swallowing, and walking. This comprehensive guide covers everything from SMA’s genetic basis, clinical symptoms, and diagnostic tests to emerging treatments and ongoing research, offering valuable insights for patients, caregivers, and medical professionals alike.
1. Introduction to Spinal Muscular Atrophy
SMA is a disorder that affects the control of muscles. It is caused by a loss of motor neurons which control voluntary muscles such as those used for eating and speaking. The loss of neurons leads to atrophy or wasting of muscles. Symptoms of SMA include children being floppy, with reduced movements, reduced head control and delayed motor milestones. Types of SMA relate to severity of weakness, age at onset of symptoms and distribution of muscles affected as well as associated problems. There are four main ‘types’ of SMA, plus rare variants [1].
Type 1 is the most severe form of SMA (Werdnig-Hoffman disease). It affects very young children (under 6 months of age). They typically have weakness and decreased movement from birth or at a very early age. Most children (90% of those not treated) develop respiratory failure by 6 months of age. This type of SMA is the most common cause of death in infancy. Affected children never sit without support [2].
1.1. Definition and Types of Spinal Muscular Atrophy
Spinal Muscular Atrophy (SMA) is a genetic degenerative disorder that affects the anterior horn cells of the spinal cord and motor nuclei of the brain stem. It is characterized by progressive muscle weakness and atrophy due to loss of anterior horn cells. At birth, all individuals possess a specific number of anterior horn cells that innervate bulk skeletal muscles. Death of these lower motor neurons after birth results in inactive denervation and subsequent atrophy of bulk skeletal muscles. The level of atrophy depends on the extent of loss of anterior horn cells. There are many neurodegenerative diseases that affect upper motor neurons, lower motor neurons, or both, but SMA is purely a hereditary autosomal recessive condition that affects lower motor neurons. SMA is classified based on age of onset and maximum functional milestones achieved prior to loss. Types I, II, III, and IV are defined by the severity and rate of disease progression. The most severe type I is further subdivided into three subtypes based on symptomology and extent of anterior horn cell involvement [1].
SMA type I (Werdnig-Hoffmann disease), the most common and severe form, accounts for approximately 50-60% of all cases. SMA type I infants are born with hypotonia and generalized weakness, including bulbar muscle weakness. They never acquire sitting ability and die from respiratory failure within the first two years of life. SMA type II (intermediate SMA) accounts for 20-30% of all cases. SMA type II children show symptoms after 6 months of age and have generalized weakness and musculoskeletal deformities. They sit but are never able to walk independently. SMA type III (Kugelberg-Welander disease) accounts for 7-10% of all cases. SMA type III children usually present with gait disturbance after 18 months of age. They are always able to walk independently but develop progressive weakness of proximal muscles. SMA type IV (adult SMA) is the rarest and mildest form, with onset occurring after age 30 and slow progression of weakness [3].
1.2. Epidemiology and Risk Factors
There are 22,452 children with SMA and 452,253 SMA carriers in the EU28 countries. The prevalence in the EU28 is 3.0 to 5.9 per 100,000 total population. Countries within the EU28 may have different estimates [4]. Epidemiology estimates are provided in several international databases and country surveys, but these may underestimate the actual number of children with SMA in resource-poor areas. No reliable epidemiological data exist for Sub-Saharan Africa, but the estimated child population is at least 97 million with a potential range of about 80–127 million children worldwide [5].
Ancestry (race, ethnicity or population), age, family history of the disease, posteromedial location, sex, body mass index (BMI), diabetes, smoking and drinking, educational level, living in urban areas, shifted sleep schedule, daylight saving time and standing work position, occupational exposure to magnetism or chemicals, pesticide or herbicide exposure, heat or physical load exposure, viral infection, and environmental pollution may increase the risk of developing diseases or exacerbate the symptoms of the disease.
2. Genetics and Pathophysiology
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of lower motor neurons in the brainstem and spinal cord leading to progressive muscle weakness and atrophy [1]. It is caused by deletion of the survival motor neuron 1 (SMN1) gene, leading to reduction of the SMN protein. SMA has been grouped into five types (0–IV) based on age of onset and clinical severity. Each type is characterized by specific clinical, genetic, and pathophysiological features. Clinical features include weakness, breathing difficulty, dysphagia, scoliosis, and joint deformities. SMA affects the proximate and distal muscles of both upper and lower extremities, although variability in severity is noted for some muscle groups (e.g., facial muscles) [6]. Most SMA studies have focused on biological alterations in the spinal cord leading to a non-cell autonomous loss of motor neuron integrity. Besides motor neuron defects and degeneration, SMA is characterized by deficits in peripheral and central nervous system processes influencing the pathogenesis of the disease. Other pathological findings comprise astrocytosis, microgliosis, thinning of ventral roots (NRs), and defects in neuromuscular junction (NMJ) pre- and postsynaptic components.
2.1. Genetic Basis of Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by the selective loss of spinal motor neurons and irreversible muscular atrophy in limb and respiratory muscles. Five genetically and clinically distinct types of SMA have been described; the most severe, type 1, is characterized by onset in infancy with loss of ability to sit unsupported and death by 2 years of age. Milder types, in which asymptomatic carriers can present with deletions in SMA genes, can present with juvenile or adult onset and possible independent ambulation until the 6th or 7th decade of life [1].
SMA is due to loss of function of the survival motor neuron 1 gene (SMN1), which is involved in the assembly of spliceosomal small nuclear ribonucleoprotein particles. For all currently known SMN loss-of-function mutations, the presence of SMN2, which arises from the same gene upon a gene conversion event, is protective against SMA. However, the type of mutation and the number of SMN2 gene copies affect the clinical severity of SMA by modulating SMN protein levels [4]. Copy number variations for SMN2 and other SMA linked genes have been described in diversified populations. Linkage analysis and long range sequencing have revealed chromosomal conformations that lead to atrophy of more than one gene within the same high-risk region.
2.2. Mechanisms of Disease Progression
A few years after SMA onset in the most common infantile type (SMA1), most children would progress to require a feeding tube and non-invasive ventilation. Surgical correction of spinal deformities is frequently needed in SMA2-3 patients at a later stage, when thoracic deformity often compromises mask ventilation. Children with later disease onset can have much longer survival and some may wish for allogenic transplantation during their teens or adulthood. Once again, disease progression from bulbar to diaphragm involvement manifests as hypoventilation and sleep-disordered breathing (SDB) following bulbar signs, requiring hospital admission for positive pressure ventilation. While all SMA patients would die as a result of ventilatory failure prior to SMN-modifying therapies, respiratory treatment has improved early- and later-treated children’s prognosis and quality of life [4]. The challenge ahead is to determine the long-term effects of treatment following various disease courses.
The hemizygous SMN1 mutation resulting in dissociated proximal muscle denervation over a few years represents a well-defined disease on a cellular and molecular level. Yet, SMA is a heterogeneous disorder. Not only different gene mutations but also different corporate modifiers (e.g. SMN2 copy number, CHRNA1 haplotype, VAMP/syntaxin SNARE complexes) lead to diverse age-of-onset disease courses and pathological sequences in the same SMN1 background. Even single core muscle fibres from SMA patients can lead to different survival times of the same treated motoneuron cassette. In the first example, juvenile SMAs arising from a different mutation in one fibre would remain normal over decades while classical Werdnig-Hoffmann SMA with a common homozygous SMN1 deletion would occur in the other myofibre, leading to cell autonomous motoneuron death within a few months [1]. Conversely, the same juvenile non-SMN defect has been shown to provoke SMA-like motoneuron effects resulting in onset of SMA.
3. Clinical Presentation and Diagnosis
Depending on when symptoms start, spinal muscular atrophy (SMA) is classified into four main types: type 1 (Werdnig-Hoffmann disease), type 2 (intermediate SMA), type 3 (Kugelberg-Welander disease), and type 4 (adult-onset SMA). In type 1 SMA, symptoms appear less than 6 months after birth and include generalized weakness, inability to sit unsupported, and poor head control. The disease is characterized by hypotonia, feeding problems, and respiratory distress [7]. Death occurs within 2 years of life, usually due to respiratory failure or aspiration. Type 2 SMA presents at 6-18 months of age and is characterized by weakness, muscle wasting, and difficulty sitting unsupported. Most patients with type 2 SMA develop scoliosis, hip dislocation, and respiratory problems. Type 3 SMA develops after age 18 months (approximately 18-24 months) and is characterized by muscle weakness, proximal muscle wasting, and difficulty standing/walking. In type 3 SMA, life expectancy is normal. Type 4 SMA is very rare and presents after 30 years of age, with only mild muscle weakness. Patients with type 4 SMA do not need a wheelchair and can lead a normal life [1].
Nerve conduction studies can differentiate SMA from other neuromuscular disorders. In patients with SMA, needle electromyography shows abnormal spontaneous potentials (positive sharp waves and/or fibrillation potentials) in more than 90% of muscles. The presence of neuropathic changes in the muscles combined with clinical findings leads to the diagnosis of SMA. Muscle biopsy shows a loss of anterior horn cells and ganglion cells or changes of muscle atrophy characteristically. SMA can also be diagnosed using genotyping methods such as polymerase chain reaction. SNP genotyping detected the deletion of 7th exon in 33 SMA patients. In southern blot analysis, the absence of SMAI gene was detected in 23 SMA patients. In multiplex PCR analysis, the deleted allele was amplified from 30 SMA patients.
3.1. Symptoms and Signs
The clinical markers used to assess spinal muscular atrophy (SMA) include: muscle weakness due to muscle wasting (atrophy) in the shoulders, hips, and initial limb girdles (bulbars); high mood degenerates, pectus excavation or contraction, stopped growth, limb cramps, and myalgias. Clinical signs involve physical examination (PE) findings. SMA can be suspected based on family history, mode of inheritance (genetic), history of pregnancy and birth, normal neonatal and temporal milestones development, and post-review conditions [1]. Diagnostic tests include electromyogram (EMG) and muscular biopsy. EMG indicates widespread limitations, with recordings of increased duration and low amplitude motor units with increased insertional activity. There are no sensory autonomic or conduction velocity limited findings. Muscular biopsy indicates widespread neurogenic atrophy and spontaneous incremental fiber size variation difference.
Other two common variants of SMA eligible for genetic studies are proximal or juvenile limb or bulb distal SMA or late onset syndromic SMA. Examination of family members is highly recommended. In the absence of carrying SMA, unaffected, obligate carriers would be homozygous normal for the normal haplotype. Siblings’ genotypes can be predicted [3].
3.2. Diagnostic Tests and Tools
There are several tests and tools that can help in the assessment and diagnosis of spinal muscular atrophy (SMA) if a doctor suspects the condition. Not all of these tests are necessary for every case; the number of tests done will depend on medical history and symptoms.
SMA Testing: In most cases, genetic testing to check for SMN1 mutations is done. A blood sample is sent to a specialized lab that can check for deletion or mutation of the SMN1 gene. Tests may also be done on amniotic fluid or chorionic villus samples (if the mother is pregnant and SMA is suspected). If negative, testing for a second copy of the SMN2 gene may be done after 12 months of age.
Electromyography (EMG): This test looks at the nerve’s electrical activity and measures how it responds to different stimuli. Nerve conduction studies (tests that check how the nerves respond to stimulation) can also be done [7].
Muscle Biopsy: A doctor takes a small sample of muscle tissue, which is examined under a microscope. In SMA, clusters (groupings) of muscle fibers become atrophic (smaller) and appear similar in size due to nerve loss.
Magnetic Resonance Imaging (MRI): This test is usually done with a 3T or higher MRI with a dedicated neuromuscular coil to detect fatty replacement (increased fat signal) in the lower, proximal muscle groups (like the hips and thighs).
Skin Fibroblast Cell Studies: This test is done in specialized labs. A small sample of skin is taken, fibroblast cells are grown in the lab, and then the cells are tested for SMN1 mutations. If absent, the cells can be tested for the second copy of the SMN2 gene [8].
These tests and tools are valuable in diagnosing spinal muscular atrophy and understanding the extent of the condition.
4. Treatment Approaches
Spinal muscular atrophy (SMA) is a genetic disorder caused by the mutation and absence of a survival motor neuron 1 (SMN1) gene, with subsequent loss of spinal motoneurons and skeletal muscle atrophy. Three main therapeutic modalities are available for the treatment of SMA, including SMN1-dependent gene transfer strategies, SMN2 splicing modulation, and SMN-independent approaches. However, little is known regarding options outside the spectrum of SMN-targeted therapies.
Current Treatment Approaches and Medications
Currently, three drugs are approved for the treatment of patients with spinal muscular atrophy: nusinersen, onasemnogene abeparvovec, and risdiplam. In addition, several other investigational treatments are in development. The therapeutic landscape of SMA has thus dramatically changed over the past years, but the safety, long-term effectiveness of these newly developed treatment options, and the best timing for therapeutic intervention are still not fully understood [2].
There is a general consensus that therapeutic interventions should be initiated as early as possible, ideally before the onset of symptoms [3]. Clinical and preclinical findings from animal models of SMA highlight the critical role of reducing SMN levels at an early stage of disease onset. For instance, transgenic mice with a low copy number of the SMN2 gene mostly develop a severe form of SMA. In these animals, the levels of SMN protein are relatively low and lead to rapid motor neuron degeneration immediately after birth. In contrast, transgenic mice with a high copy number of the SMN2 gene exhibit late-onset or mild disease phenotypes.
Thus, many of the newly developed SMA therapies are currently offered to patients at young ages. However, whether such an approach is safe and effective in the context of each specific therapeutic modality has not yet been clarified. With the rapid approval of multiple treatment options, there is an increased need for comprehensive information on each of the available therapies and on the prospects for combination or sequential applications.
4.1. Current Therapies and Medications
Spinal muscular atrophy (SMA) is a rare genetic disorder with a relevant unmet medical need. Out of the estimated 125,000 patients suffering from SMA type I in the US, Europe, and Asia, a small fraction is currently receiving treatment. Medical compounds currently in use or under investigation fall into two groups, those targeting SMA dysfunction directly and those addressing the consequences thereof [9]. Other therapies and medications in preclinical studies aim at disease prevention through early detection and subsequent intervention using non-pharmacological treatment options [2].
The SMA disease process may be slowed down, stopped, or reversed in its effects on other tissues, if the systemic use of compounds increasing SMN levels results in unobstructed accessibility of tissues outside the CNS. Therefore, substances that readily cross the blood-brain barrier and address the mechanisms influencing SMN levels outside the CNS will be one avenue of interest in the development of supportive compounds for SMA in the future. Several pharmacological compounds that target potential downstream consequences induced by impaired SMN have been reviewed previously. With a significant mechanistic diversity, the pharmacological candidates address either neuroprotective or muscle-enhancing actions, and some have entered early clinical trials.
4.2. Emerging Treatments and Research
The recent approval of gene-targeted therapies, including nusinersen, onasemnogene abeparvovec, and risdiplam, has modified the SMA treatment landscape. Nusinersen, the first approved drug, is an injected antisense oligonucleotide that modifies SMN2 pre-mRNA splicing [2]. Onasemnogene abeparvovec is an approved gene therapy for SMA types 1 and 2 that uses an adeno-associated virus 9 vector to deliver a copy of SMN1. Both therapies have shown unprecedented efficacy in slowing disease progression when given before symptom onset. Risdiplam, an oral splicing modifier that has the potential to treat adult SMA patients, is awaiting approval. Other investigational drugs targeting SMN2 splicing are in clinical trials. Collective efforts among pharmaceutical industries, research centers, and patient advocacy groups have expedited the translation of scientific discoveries into clinical benefits. Understanding the diverse mechanisms of actions employed by each therapeutic strategy is key to optimizing treatment regimens, integrations, and timelines.
SMN-Independent Targets
Currently available SMN-modulating therapies are not curative; they only slow disease progression. Several ongoing research efforts focus on investigating alternative SMN-independent therapeutic strategies for SMA. SMN loss affects various cellular and molecular pathways that could be targeted for SMA treatment [10]. These nonclassical strategies, including sustained activation of specific neurotrophic signaling pathways, are mainly under investigational studies of candidate compounds in preclinical stages. SMN knock-down models of Drosophila and C. elegans recapitulate a wider class of pathways relevant in the SMA context. These novel approaches to SMA treatment exhibit diverse mechanisms of action, including SMN protein stabilization, small molecules that compensate splicing abnormalities in alternative exons, the inhibition of ribonucleases and other proteins, strategies for promoting axon growth/beyond loss of motor neurons, and the overexpression of factors that counteract the pathological roles of ATXN2 and Berthold in metal homeostasis. Though less explored than SMN-targeting interventions, therapeutic strategies targeting SMA disease modifiers may augment the existing arsenal of SMA therapies and enhance treatment efficiencies.
5. Multidisciplinary Care and Support
Multidisciplinary care is a key component of spinal muscular atrophy (SMA) management. It involves employing a wide range of health professionals to meet the care needs of individuals with SMA. Knowledge of the roles and expertise of other specialists within the team and how to effectively access this input will assist in optimizing overall care. Current evidence outlines the key clinical assessments, medical care, therapy, and social care interventions that should be available to all individuals with SMA. There has been a strong drive to unify and standardize the delivery of SMA care systems worldwide [5]. A number of initiatives supported by the World SMA Foundation Association and funded by organizations including the United States SMA Coalition, SMA Europe, SMA Reach for a Cure, and the SMA UK Coalition have been undertaken to advance global strategies for the development of multidisciplinary care in community settings.
Numerous international patient organizations exist to provide education and support to patients and families affected by SMA. Peer organizations can deliver support in many areas, including access to health insurance, the provision of wheelchairs, and social integration. Access to specialist organizations knowledgeable about SMA is helpful to families, as they provide a positive influence throughout the situation [11]. Multidisciplinary care should be built on the principles that the care is holistic, evidence-based, and family-centered. Families and individuals with SMA should have easy access to a full range of tried and tested support services. Health services should work in partnership with families and local support services to provide comprehensive care.
5.1. Role of Healthcare Providers
In spinal muscular atrophy (SMA), the roles of healthcare providers in delivering multidisciplinary care to affected individuals include physician, nurse, physiotherapy, occupational therapy, speech therapy, dietetic, psychology, spinal orthosis, and wheelchair assessments. All disciplines offered their input to wider and more integrated patient care [5]. The role of key professionals and their contributions are summarized below.
The healthcare professional leading the SMA multidisciplinary team is the Physician. The SMA consultant Physician collates all necessary contributions and recommendations prior to the clinical consultation appointment. Aside from seeing the patient twice during consultation days, the physician is in contact with the family on a need-be basis. Concerned disciplines are invited to attend a family consultation. The Physician oversees all other healthcare providers’ involvement in each child’s multidisciplinary management plan. The physician is also responsible for feeding and reflux assessments (e.g. gastrostomy, fundoplication) and attending patients’ hospital admissions as needed. Importantly, the Physician keeps records of each affected child’s multidisciplinary care plans and writes annual review letters to the family and their own physician. GP’s are also closely involved with any medical management needs outside of the specialists’ recommendations [12]. A proactive, open-door policy is encouraged for any medical concerns.
5.2. Support Services for Patients and Families
Support services for individuals diagnosed with spinal muscular atrophy (SMA) and their families are available from a variety of resources, including national organizations, local and regional groups, and individual clinics and centers. Most of these groups provide informational pamphlets and fact sheets and will refer patients and family members to appropriate sources of information and assistance.
SMA Support Services
The SMA Foundation is a non-profit organization created to support research aimed at developing a treatment for SMA. The Foundation works with pharmaceutical companies and other academic scientists to facilitate the development of therapies for SMA. In addition, the Foundation is involved in outreach, education, and advocacy. The Foundation provides a Co-Pay Assistance Program for families enrolled in public or private insurance who have difficulty meeting their out-of-pocket expenses for Spinraza (nusinersen) infusions. The Foundation’s website includes scientific and clinical research news, as well as resource links, publications, and related organizations [2].
The Muscular Dystrophy Association (MDA) helps patients with muscle diseases, including SMA. The MDA coordinates care at more than 200 neuromuscular clinics in the United States and provides families with access to multi-disciplinary care, referrals to experienced specialists, and information related to medical issues, programs, and services. The MDA’s website includes a variety of resources, including assistive technology, financial assistance programs, and industry contacts [3].
6. Quality of Life and Wellness
Optimizing quality of life and wellness is crucial for individuals affected by spinal muscular atrophy (SMA). Quality of life refers to the general wellbeing of individuals and societies. Multiple factors contribute to the quality of life of individuals, ranging from health to economic stability. Physical and occupational therapy is essential for improving quality of life. A well-planned therapy program enhances mobility, coordination, balance, strength, and flexibility. Access to modified equipment, home modifications, and assistance with activities of daily living ensures independence. Nutritional support is critical for enhancing quality of life [2]. Weight management, dietary considerations, utilizing commercial supplements, and seeking advice from dieticians positively impact the wellbeing of individuals with SMA. SMA has physical, emotional, and psychosocial effects on the patients and their families. Therefore, a holistic approach is essential for empowering individuals with SMA and seeking proper financial and emotional support.
Overall wellness is a state of being in good health that is not a solitary achievement but a combination of many things over time. There is a balance between physical, emotional, spiritual, and financial wellness. SMA can affect the overall wellness of individuals, and thus, proper care is essential. While medical questions about SMA can be addressed, individual choices cannot. Family members’ attitudes towards SMA, indifference, agnosticism, acceptance, and fatalism play different roles in living with SMA. A strict treatment regimen may be followed, but it may not bring wellness or inner peace [13].
6.1. Physical and Occupational Therapy
[2]. Early intervention increases the likelihood of improved outcomes, and the size of the therapeutic window for recommended/required interventions progressively becomes smaller with advancing age and progression of the disease. Physical and Occupational therapy and training: Knowledge is vital to improve outcomes. Affected individuals or families with a recent diagnosis or in close contact with diagnosed individuals should be informed/directed to expert centres. Families should be educated to identify other early signs of disease progression or complications as SMA progresses [3].
6.2. Nutritional Support and Diet
The significance of nutritional support and dietary considerations is paramount in the comprehensive care of individuals affected by spinal muscular atrophy (SMA) [5]. Specific dietary interventions and nutritional support are essential for capturing and addressing the unique needs and challenges confronting individuals with SMA in the domain of nutrition. SMA is a rarity in that the population and markets serviced by this rare disease are now reversing the previous trends of the targeting of adult and pediatric populations, and with it, attention to nutrition and dietary management concerning overall health and wellness. It is now a time of significant potential in SMA as a field of neurodegenerative diseases with the availability of emerging therapies and the finish line of the clinical promise of this care paradigm [14]. As such, the architecture of nutritional science and practice in SMA is being nurtured in tandem with care, approaches, and interactions which are present in other much more common global diseases. The window is open to share knowledge and efforts as part of a community in SMA.
7. Future Directions in SMA Research
Understanding the future directions in the field of spinal muscular atrophy (SMA) research is crucial for both physicians and patients to monitor the latest breakthroughs and developments. SMA is a devastating motor neuron disease that results from the loss of motor neuron anterior horn cells in the spinal cord and is caused by a deficiency of the survival motor neuron (SMN)1. While the clinical phenotype of SMA is mainly determined by the gene dosage of SMN2, an identical paralog of SMN1 that lacks 90% full-length SMN (SMNfl) due to alternative splicing, additional gene mutations have a modifying effect on SMA phenotype. The transacting factors involved in SMN alternative splicing, such as heterogeneous ribonucleoproteins, spliceosome components, and RNA-binding proteins, are under investigation to determine their interaction with microRNAs (miRs) or lncRNAs in SMA [3].
Gene therapy has made significant strides in SMA treatment, and SMA screening initiatives have also been established. Dubowitz refers to the new SMA treatments that are becoming available as ‘the war on SMA’ [2]. Despite the optimism offered by these exciting findings, much remains unknown. With the onset of these new treatments, additional challenges and questions on several fronts will need to be addressed. Would T1-T2/3 pre-symptomatic patients be best treated with intrathecal (IT) nusinersen or systemic-onasemnogene abeparvovec in view of the T2-early-nusinetn safety study? Would T4 patients continue to be eligible for nusinersen in view of the post-marketing report on T4/young children? Would onasemnogene abeparvovec be feasible for older patients? Recommendations for dose and timing of nusinersen vs. onasemnogene abeparvovec will need to be tested. Would SMA phenotypes other than SMA-1 such as T2-bulbar patients be equally eligible for treatment? Overall, a concerted analysis of a dataset encompassing clinical care, natural history, and genomic/molecular biomarkers for SMA would offer the best chance to determine the appropriate path forward as SMA-SC has embarked on and lead to personalized clinical studies and trials for SMA.
7.1. Advancements in Gene Therapy
The complete loss of SMN is common in all types of SMA. SMA mice were introduced with a target SMN1 gene delivery, via AAV8 vectors, under the control of an astrocyte-selective GFAP promoter. SMA had a profound effect in astrocytes by preventing mutations in SMN1 in astrocytes but not in neurons, reducing the levels of TNF-α, IL-4, and IL-10 cytokines, and prolonged the lifespan, mobility, muscle strength, and body weight of SMA mice compared to non-injected SMA mice [15]. Several treatments for SMA, including genetically engineered SMN mini-genes, artificial motorneurons that produce SMN in therapeutic concentrations, small-molecule compounds targeting substrate synthesis and posttranslational modification, and novel viral vectors are being tested in the preclinical setting. For example, promising results were obtained using rAAV9 vectors encoding an SMN mini-gene and an adeno-associated virus serotype 2 (AAV2) vector delivering the SMN2 transgene under the control of a promoter with inner ear specificity. The routes of administration, dosing frequency, and mechanisms of action vary across all methods under development, exploring the possibilities of neuroprotection, improvement of muscle strength and function and various methods of modulation of full-length SMN protein levels.
In several studies, different drug candidates such as valproic acid were tested for their ability to treat SMA. In one study, valproic acid, a histone deacetylase inhibitor, was shown to be able to increase SMN protein expression multiple times in fibroblasts obtained from patients with SMA. In an SMA model mice, the treatment with this drug led to an increase in the average survival rate (for 14 days). However, this drug had side effects, which were mainly related to weight gain (8 grams on average for 16 days), which were associated with changes in the motor function of the animals model and refusal of further testing of this drug. Current treatments for SMA, currently at various stages of preclinical and clinical research, are being explored. There are many methods under development. So far they vary in route of administration, dosing frequency, and mechanisms of action, but the majority of them, if not all, aim at restoring the SMN expression and full-length SMN protein levels in a cell [2].
7.2. Clinical Trials and Collaborative Efforts
The completed clinical trials as well as ongoing clinical trials are summarized in a tabular form, along with an explanation of the industry-led collaborative initiatives in the research ecosystem [9]. As efforts to address spinal muscular atrophy (SMA) gain momentum, an overview of completed and ongoing clinical trials provides an insight on the therapeutic landscape. The completed clinical trials are tabulated on the YA SMA platforms with design details, safety and tolerability results followed by the potential outcomes that can be expected from these trials culminating in SMA treatments. Details about ongoing clinical trials including their designs and targets are discussed [2]. The industry-led collaborative initiatives in the SMA research ecosystem are covered elaborately to provide a coherent view of collective efforts by pharmaceutical companies, research organisations, foundations, and healthcare institutes to propel SMA research forward. The collaborative efforts focus on key constituents of SMA management that include newborn screening, biomarker identification, and patient registries that provide better recruiting platforms for clinical trials. Some planned initiatives such as surveys/studies that are still in nascent stages are mentioned to bridge any gaps in the proposed plans in SMA. The impetus is on SMA, although several ongoing efforts are pilot-programs that target broader neurological disorders/conditions. Providing an overview on completed clinical trials, ongoing clinical trials, and collaborative initiatives not only helps keep abreast of the latest advancements; but also provides an opportunity to be informed about potential means of SMA management.
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