Spinal Muscular Atrophy Therapy Research Articles

Precision medicine in Australia: now is the time to get it right.

Precision medicine in Australia: now is the time to get it right.

Newborn screening and gene therapy in SMA: Challenges related to vaccinations.

Spinal muscular atrophy (SMA) affects one in 7,500-10,000 newborns. Before the era of disease-modifying therapies, it used to be the major genetic cause of mortality in infants. Currently, there are three therapies approved for SMA, including two molecules modifying the splicing of the SMN2 gene and one gene therapy providing a healthy copy of the SMN gene with a viral vector. The best effects of any of these therapies are achieved when the treatment is administered in the presymptomatic stage of the disease, therefore newborn screening programs are being introduced in many countries. Patients identified in newborn screening might be eligible for gene therapy. However, gene therapy and the associated administration of steroids in newborns might interfere with the vaccination schedule, which includes live immunization against tuberculosis in some countries. The timing of gene therapy in patients who received live vaccinations has not yet been addressed neither in the clinical trials nor in the existing international guidelines. The Polish Vaccinology Association has developed the first recommendations for gene therapy administration in newborns who received live vaccination against tuberculosis. Their statement was implemented in the current guidelines for Polish SMA patients identified in the newborn screening program and might be helpful for medical professionals in other countries where live vaccine against tuberculosis is still in routine use in newborns.

Gene Therapies for Spinal Muscular Atrophy and Duchenne Muscular Dystrophy: A Pathbreaking Moment in Therapeutics

Background: Gene therapy has proved to be a boon for neuromuscular diseases. A concept introduced in the early 1960’s, has been put into clinical practice in the past 5-10 years. The process by which a healthy gene replaces a defective gene in a human body through vectors is truly pathbreaking. Patients with inherited degenerative neuromuscular disorders such as spinal muscular atrophy, and muscular dystrophies undergo progressive deterioration and eventually death. Gene therapy and other adjunctive clinical approaches have provided such patients with a second chance to truly live their life. This review is centered on the different gene therapies currently developed for spinal muscular atrophy and Duchenne muscular dystrophy and also sheds light on the emerging therapies.
 Methods: Literature search was done in Medline, Embase, and Google Scholar. The relevant and important articles were included for developing the narrative review. 
 Results and Discussion: The nusinersen, risdiplam, zolgensma, eteplirsen, golodirsen, viltolarsen, casimersen and ataluren are developed as gene therapies for Spinal muscular atrophy and Duchenne muscular dystrophy. The therapies approved under orphan drug designation have shown muscle strength improvement in clinical trials. However, long-term data on safety and efficacy is to be determined. The cost of the therapies acts as an impediment in most cases.
 Conclusion: The development of gene therapies for inherited genetic disorders would be a prelude for several other genetic diseases. The studies in this arena would provide a prototype for translational research from bench to bedside. Further efforts are mandated towards long term safety, efficacy, and affordability of therapies.

Bridging the Gap: Gene Therapy in a Patient With Spinal Muscular Atrophy Type 1.

Molecular therapies exploit the understanding of pathogenic mechanisms to reconstitute impaired gene function or manipulate flawed RNA expression. These therapies include (1) RNA interference by antisense oligonucleotides, (2) mRNA modification using small molecules, and (3) gene replacement therapy, the viral-mediated intracellular delivery of exogenous nucleic acids to reverse a genetic defect. Several molecular therapies are approved for treating spinal muscular atrophy (SMA), a recessive genetic disorder caused by survival motor neuron (SMN)1 gene alterations. SMA involves degeneration of lower motor neurons, which leads to progressive muscle weakness, hypotonia, and hypotrophy. Onasemnogene abeparvovec is a gene replacement therapy for SMA that uses adeno-associated virus delivery of functional SMN1 cDNA to motor neurons. Two other molecular therapies modulate SMN2 transcription: nusinersen, an antisense oligonucleotide, and risdiplam, a small molecule designed to modify faulty mRNA expression. The most suitable individualized treatment for SMA is not established. Here, we describe remarkable clinical improvement in a 4-month-old patient with SMA type 1 who received onasemnogene abeparvovec therapy. This case represents an explanatory bridge from bench to bedside with regard to therapeutic approaches for genetic disorders in neurology. Knowledge of the detailed mechanisms underlying genetic neurologic disorders, particularly monogenic conditions, is paramount for developing tailored therapies. When multiple disease-modifying therapies are available, early genetic diagnosis is crucial for appropriate therapy selection, highlighting the importance of early identification and intervention. A combination of drugs, each targeting unique genetic pathomechanisms, may provide additional clinical benefits.

The ethics of crowdfunding in paediatric neurology.

In the last decade, there has been a dramatic increase in the number of families resorting to internet-based public appeals to fund access to novel, highly expensive, or experimental therapies for rare disorders. Medical crowdfunding may provide a means to fund treatments or interventions, but it raises individual and societal ethical questions. In this review, we consider the ethical challenges crowdfunding poses in paediatric neurology, drawing on the example of gene therapy for spinal muscular atrophy. We discuss physician responsibilities, and how neurologists should respond to crowdfunding that they encounter in clinical practice. We also briefly consider actions that can be taken by clinicians, charities, and crowdfunding websites to reduce harms. The best way to mitigate these harms may be to target the high costs and restrictive criteria that limit access to many novel treatments, and to optimize treatment utility, for instance by newborn screening. WHAT THIS PAPER ADDS: Crowdfunding is a social phenomenon arising from families' inability to access desired treatment. Treatments sought by crowdfunding range from those that are clearly beneficial (but unaffordable) to those that would be ineffective and potentially harmful. Crowdfunding carries a range of harms and risks to families and children and has wider social impact.

Flexible endoscopic evaluation of swallowing in children with type 1 spinal muscular atrophy

PurposeThis study aimed to report on implementing flexible endoscopic evaluation of swallowing (FEES) in infants and toddlers with type 1 spinal muscular atrophy (SMA). In addition, a comparison of FEES results and clinical scores was carried out.MethodsA prospective pilot study was conducted including ten symptomatic children with SMA type 1 (two SMN2 copies). They started treatment with one of the three currently approved therapies for SMA at a median age of 3.8 months (range 0.7–8.9). FEES was performed according to a standard protocol using Penetration–Aspiration Scale (PAS) and Murray Secretion Scale as a primary outcome. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) for motor function, Neuromuscular Disease Swallowing Status Scale (NdSSS), Oral and Swallowing Abilities Tool (OrSAT), and single clinical swallowing-related parameters were also assessed.ResultsDistinct swallowing disorders were already evident in eight children at inclusion. The most common findings from FEES were pharyngeal secretion pooling, penetration, and aspiration of saliva and food as well as delayed initiation of swallowing. Despite an average increase in motor function, no comparable improvement was found in swallowing function. None of the surveyed clinical scores showed a significant dependence on PAS in a mixed linear model.ConclusionsValuable information regarding the status of dysphagia can be gathered endoscopically, particularly concerning secretion management and when oral intake is limited. Currently available clinical tools for children with type 1 may represent a change in nutritional status but are not yet mature enough to conclude swallowing ability. Further development is still required.

Complex Neuropsychiatric and Laboratory-Instrumental Diagnostics in Determination of Tactics of Therapeutic Management of Patients with Spinal Muscular Atrophy: Regional Experience

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare hereditary disabling disease and the most common hereditary cause of infant deaths. The timely comprehensive diagnosis of SMA permits to plan therapeutic tactics and preserve the quality of patients life. One of the objectives of the given work is a review of the actual literature data on etiopathogenesis, clinical presentation, valid diagnosis and modern effective tactics of SMA management.
 AIM: To evaluate the management tactics of patients with SMA taking into account neuropsychiatric symptoms, to analyze problems of proposal and organization of measures aimed at improvement of the quality of medical care, on the basis of the practical experience of the Samara region and with consideration of the current state of the problem.
 MATERIALS AND METHODS: In the work, the data of the archive of Seredavin Samara Regional Clinical Hospital were analyzed, 132 medical histories of 77 patients were processed with discharge dates from January 2008 to February 2022 with the following diagnoses (according to the code of the International Classification of Diseases and Health Related Problem, 10th revision (ICD-10)): G12.0 (spinal muscular atrophy, type I [WerdnigHoffmann disease], G12.1 (other hereditary SMA), G12.8 (other SMA and related syndromes) and G12.9 (unspecified SMA). The analysis of the results of clinical, laboratory, instrumental and neuropsychiatric diagnostic methods was performed in comparison with the tactics of therapeutic management of these patients. For statistical processing of the data, methods of descriptive statistics were used.
 RESULTS: Socio-demographic data. As of February 2022, 58 patients were registered (mean age 38.4 (41.3) years, of them 32 (55.2%) were individuals of female gender including 21 children (mean age 12.3 (7.4) years, 14 (24.1%) girls), with the following diagnoses according to ICD-10: G12.0 (n = 7; 12.0%; only children), G12.1 (children: n = 14; 24.1%; adults: n = 29; 50.0%), G12.8 (n = 6; 10.3%; only adults), G12.9 (n = 2; 3.4%; only adults). Clinical data. Motor disorders from a mild proximal lower paraparesis (n = 13; 22.4%) to pronounced tetraparesis (n = 7; 12.0%). The study of mental status was limited to evaluation of the state of consciousness and effectiveness of contact. Data on therapy. Until 2021, symptomatic therapy of SMA was conducted in the region, since March 2021, 8 children (13.8% of the total sample) aged 7.3 (8.8) years received nusinersen, another 8 children (13.8%) aged 9.5 (6.9) years received risdiplam; parents of 3 more children (5.2%) refused taking drugs. Of adult patients (n = 37; 63.8%; 35.3 (23.6) years) with confirmed SMA 5q (n = 10; 17.2%, 35.3 (19.0) years), 1 patient received nusinersen, the rest 9 patients (15.5%) did not receive therapy, 3 (5.2%) were achieving the right to receive drugs (at the moment of the analysis).
 CONCLUSION: The data analysis revealed deficit of early SMA diagnosis (at the moment of the diagnosis, all the patients were already having pronounced symptoms), of assessment of affective and cognitive disorders, monitoring of treatment effectiveness (absence of validated scales for motor skills assessment), and also showed low availability of treatment for adult patients, which requires reorganization of care of patients with SMA in the region taking into account the revealed factors).

Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy.

Intrathecal delivery of Nusinersen–an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction–is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.

FP.10 Combination of BIO101 with antisense oligonucleotide therapy demonstrates synergistic beneficial effects in severe SMA-like mice

Spinal Muscular Atrophy (SMA) is a neurodegenerative disease characterized by the loss of spinal motor neurons and progressive muscular atrophy, due to insufficient level of survival of motor neuron protein (SMN). SMA is defined as a non-cell autonomous disease, involving numerous tissues and cell-types, including skeletal muscles. In this context, strategies to overexpress SMN protein and approaches to maintain neuromuscular functions are currently developed and appear as promising long-term prospect for therapy in SMA. We evaluated the efficacy of Sarconeos (API BIO101), a Mas receptor activator, as monotherapy and in combination with ASO therapy in severe SMA-like mice (Smn^Δ7/Δ7; 2 copies SMN2^+/−). We showed beneficial effects of BIO101 as monotherapy on the entire motor unit with a complete protection of lumbar motor neurons, a limited muscular atrophy (-17% in the tibialis, -40% in the plantaris, and -12% in the soleus), an increased vascularization (+10% in the tibialis and the plantaris, +3% in the soleus), and an accelerated maturation of both muscular fibers and neuromuscular junctions. Interestingly, these benefits were independent of SMN expression. In combination with ASO therapy, BIO101 demonstrated synergistic effects on body weight (+1% with BIO101, +11% with ASO, +32% with ASO + BIO101 at 10 days after birth compared to vehicle) and increased survival (+5 days of median survival). Most importantly, the co-treated SMA-like mice improved their moving capacity (+40%) and their fatigue resistance (4,2-fold) compared to SMA-like mice treated only with ASO. These results provide strong evidence that BIO101, with beneficial effects on the entire motor unit, constitutes an efficient SMN-expression-independent therapy for improving muscle function and should be considered as a potential combinatorial option for a new therapeutic strategy in SMA patient.

P.37 Outcomes in patients with spinal muscular atrophy and four or more SMN2 copies treated with onasemnogene abeparvovec: Findings from RESTORE

Onasemnogene abeparvovec (OA) is a one-time gene replacement therapy for spinal muscular atrophy (SMA). While clinical trials of OA included patients with two or three SMN2 gene copies, patients with four or more copies may be treated in clinical practice. Natural history and outcomes following SMA treatment have not been well-characterized for these patients. We sought to describe clinical outcomes after OA monotherapy for patients with four or more SMN2 copies in RESTORE, a prospective SMA registry. We evaluated baseline characteristics, and post-treatment motor function, motor milestone achievement, use of ventilatory/nutritional support, and adverse events (AEs). Patients evaluable for motor function or milestone achievement had ≥2 assessments, with ≥1 after OA. Seven children with four SMN2 copies and five with more than four copies were included. All 12 cases were identified by newborn screening in the United States and treated presymptomatically. Median age at OA was 3 months (range, 1–11). Two of three children with evaluable motor milestone assessments achieved new milestones. All three children evaluable for CHOP INTEND maintained or achieved the maximum score of 64 points. One child was evaluable for HINE and achieved a 6-point increase. Five children with recorded AE data had ≥1 treatment-emergent AE (mainly Grade 1 LFT and/or troponin elevations without relevant clinical signs). Two children reported AEs ≥Grade 3 (one had otitis media and one with history of fetal stroke had seizure ∼3.5 months post-OA). No deaths or use of ventilatory/nutritional support were reported. Patients with four or more SMN2 gene copies attained improvements in motor function and achieved new milestones after treatment with OA. Presentation of SMA with four or more SMN2 copies is heterogeneous, and laboratory determination of SMN2 copy number may be unreliable, highlighting the importance of early identification and intervention to optimize outcomes for all SMA patients.

O.09 Gene therapy of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME)

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is an autosomal recessive disorder caused by mutations in the <i>ASAH1</i> gene, which codes for acid ceramidase (ACD), a lysosomal enzyme that catalyses the bioactive lipid ceramide into sphingosine and fatty acid. The disease is progressive, starting during childhood with muscle weakness and/or myoclonic seizures, and leads to death in most cases at teenage. To date, there is no curative treatment and therefore a clear unmet medical need. In the present study, we evaluated a gene therapy approach in a mouse model of acid ceramidase deficiency. We report that intravenous administration of a recombinant AAV9 vector expressing human ACD in diseased <i>Asah1</i>^P361R/P361R mice prolonged survival of all animals until the end of a 6-month study, restored body growth and motor activity, and abolished inflammation in peripheral tissues and the central nervous system. Our findings provide proof-of-concept that systemic AAV-mediated <i>ASAH1</i> gene replacement can correct the severe phenotype of a mouse model of acid ceramidase deficiency, paving the way for clinical translation in patients.

Onasemnogene Abeparvovec in Type 1 Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis.

One of the latest approved therapies for spinal muscular atrophy (SMA) is onasemnogene abeparvovec, which transduces motor neurons with the survival of motor neuron gene. The aim of this meta-analysis was to estimate the effect of onasemnogene abeparvovec on motor function in participants with type 1 SMA. Medline, Web of Science, Scopus, and Cochrane Library were searched for studies published from inception to August 2022. Pre-post clinical trials and observational studies determining the effect of onasemnogene abeparvovec on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score or motor milestones (i.e., head control, sit unassisted, feed orally, not use permanent ventilatory support, crawl, stand alone, and walk alone) in participants with type 1 SMA were included. Continuous outcomes (i.e., CHOP-INTEND score) were expressed as pre-post mean difference and 95% confidence interval (CI), while the proportion of participants who achieved >40, >50, and >58/60 points on the CHOP-INTEND and the achievement of the motor milestones were expressed as proportions and 95% CI. A random effects meta-analysis was conducted on each outcome, and the baseline CHOP-INTEND score was considered a covariate. Eleven studies were included in the systematic review, and four were included in the meta-analyses. Onasemnogene abeparvovec improved CHOP-INTEND scores by 11.06 (9.47 to 12.65) and 14.14 (12.42 to 15.86) points at 3 and 6 months postinfusion, respectively. Moreover, 87%, 51%, and 12% achieved CHOP-INTEND scores of >40, >50, and >58/60 points, respectively. However, this proportion increased to 100% in presymptomatic participants with greater baseline CHOP-INTEND. Motor milestones were also improved, especially in presymptomatic participants. Our systematic review not only showed a marked improvement in motor function in type 1 SMA but also showed that treatment in the presymptomatic stage improves the development of these children toward an evolution close to normal for their age.

Investigating attitudes toward prenatal diagnosis and fetal therapy for spinal muscular atrophy.

In utero SMA treatment could improve survival and neurologic outcomes. We investigated the attitudes of patients and parents with SMA regarding prenatal diagnosis, fetal therapies, and clinical trials. A multidisciplinary team designed a questionnaire that Cure SMA electronically distributed to parents and patients (>18years old) affected by SMA. Multivariable ordinal logistic regression was used to analyze associations between respondent characteristics and attitudes. Of 114 respondents (60% of whom were patients), only 2 were prenatally diagnosed. However, 91% supported prenatal testing and 81% felt there had been a delay in their diagnosis. Overall, 55% would enroll in a phase I trial for fetal antisense oligonucleotide (ASO) while 79% would choose an established fetal ASO/small molecule therapy. Overall, 61% would enroll in fetal gene therapy trials and 87% would choose fetal gene therapies. Patients were less likely to enroll in a fetal gene therapy trial than parents enrolling a child (OR 0.31, p<0.05). Older parental age and believing there had been excessive delay in diagnosis were associated with an interest in enrolling in a fetal ASO trial (OR 1.04, 7.38, respectively, p<0.05). In utero therapies are promising for severe genetic diseases. Patients with SMA and their parents view prenatal testing and therapies positively, with gene therapy being favored.

Glial fibrillary acidic protein in cerebrospinal fluid of patients with spinal muscular atrophy.

ObjectiveActivated astroglia is involved in the pathophysiology of neurodegenerative diseases and has also been described in animal models of spinal muscular atrophy (SMA). Given the urgent need of biomarkers for treatment monitoring of new RNA‐modifying and gene replacement therapies in SMA, we examined glial fibrillary acidic protein concentrations in cerebrospinal fluid (cGFAP) as a marker of astrogliosis in SMA.Methods58 adult patients and 21 children with genetically confirmed 5q‐associated SMA from four German motor neuron disease specialist care centers and 30 age‐ and sex‐matched controls were prospectively included in this study. cGFAP was measured and correlated to motor performance and disease severity. Additionally, we compared cGFAP with neurofilament light chain concentrations in cerebrospinal fluid (cNfL).ResultscGFAP concentrations did not differ from controls but showed higher levels in more severely affected patients after adjustment for patients' age. Normalized cNfL values were associated with disease severity. Within 14 months of nusinersen treatment, cGFAP concentrations did not change, while cNfL decreased significantly.InterpretationcGFAP is not an outstanding biomarker in SMA, but might support the hypothesis that glial activation is involved in SMA pathology. Unlike previously suggested, cNfL may be a promising biomarker also in adult patients with SMA, which should be subject to further investigations.

The importance of SMA screening tests in newborns – review

Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease caused by the loss of alfa motor neurons occuring with a frequency of 1 of 11000 births. It leads to muscular weakness and is cause of high rate of mortality in children. 95% cases of SMA are caused by homozygous deletion in SMN1 which is identified as the SMA disease-determining gene. The number of copies of SMN2 determines the phenotype of the disease. Screening tests for SMA can detect 95-98% of the mutations in SMN1, but cannot detect point mutations. The SMA genetic tests are characterized by high sensitivity and specificity, they are inexpensive and therefore can be used on a large scale. Generally DNA is isolated from the dry blood spot and then subjected to PCR analysis. The SMN2 copy number is determined using the MLPA technique. Screening tests allow the diagnosis of SMA even before the onset of symptoms. Numerous scientific studies show that early treatment in most patients with detected SMA allows for better neuromotor development in children. The most beneficial effects of the SMA therapy are visible in patients treated pre-symptomatically - and this is only possible thanks to the use of screening tests. In this review we present the importance of SMA screening tests in newborns according to the latest scientific reports.

Muscle quantitative MRI in adult SMA patients on nusinersen treatment: a longitudinal study.

The recent approval of disease-modifying therapies for spinal muscular atrophy (SMA) raised the need of alternative outcome measures to evaluate treatment efficacy. In this study, we investigated the potential of muscle quantitative MRI (qMRI) as a biomarker of disease progression in adult SMA3 patients during nusinersen treatment. Six adult SMA3 patients (age ranging from 19 to 65 years) underwent 2-point Dixon muscle qMRI at beginning of nusinersen treatment (T0) and after 14 months (T14) to evaluate the muscle fat fraction (FF) at thigh and leg levels; patients were clinically assessed at T0 and T14 with the Hammersmith Functional Rating Scale Expanded (HFMSE), the Revised Upper Limb Module (RULM) and the 6-minute walk test (6MWT). At T0, vastus lateralis muscle displayed the highest mean FF (67.5%), while tibialis anterior was the most preserved one (mean FF = 35.2%). At T0, a slightly significant correlation of FF with HFMSE (p = 0.042) and disease duration (p = 0.042) at thigh level and only with HFMSE (p = 0.042) at leg level was found. At T14, no significant change of mean FF values at thigh and leg muscles was found compared to T0. Conversely, a statistically significant (p = 0.042) improvement of HFMSE was reported at T14. We observed no significant change of FF in thigh and leg muscles after 14 months of nusinersen therapy despite a significant clinical improvement of HFMSE. Further studies with longer follow-up and larger cohorts are needed to better investigate the role of qMRI as marker of disease progression in SMA patients.

Modulation of DNA transcription: The future of ASO therapeutics?

In this issue of Cell, Kornblihtt and colleagues report a strategy to improve antisense oligonucleotide spinal muscular atrophy therapy. They discover that the oligonucleotide drug nusinersen, which induces exon inclusion, also promotes repressive chromatin modifications, which in turn work against exon inclusion. Notably, co-administration of histone deacetylase inhibitors counteracted this effect to augment exon inclusion.

Commentary: Current Status of Gene Therapy for Spinal Muscular Atrophy.

Commentary: Current Status of Gene Therapy for Spinal Muscular Atrophy.

Onasemnogene abeparvovec for the treatment of spinal muscular atrophy

ABSTRACT Introduction Gene therapy for spinal muscular atrophy (SMA) represents a significant milestone in the treatment of neurologic diseases. SMA is a neurodegenerative disease that results in motor neuron loss because of mutations of the survival motor neuron 1 gene, which directs survival motor neuron (SMN) protein production. Onasemnogene abeparvovec, a one-time gene replacement therapy, delivers a functional transgene to restore SMN protein expression. Onasemnogene abeparvovec has demonstrated improved survival and motor milestone achievements for presymptomatic infants and patients with SMA type 1. Areas covered This expert review describes the current state of gene therapy for SMA, reviews the mechanism of and clinical experience with onasemnogene abeparvovec, explains future efforts to expand applications of gene therapy for SMA, and provides context for developing gene therapy for other conditions. Expert opinion Onasemnogene abeparvovec has demonstrated efficacy in clinical trials and, because of this, is a valuable treatment option for patients with symptomatic infantile SMA and those identified by newborn screening. Gene therapy is still in its infancy, and challenges and uncertainties associated with transgene delivery must be addressed. With ongoing development of vector technology, more specific tissue tropism, reduced ‘off-target’ effects, and an enhanced safety profile will continue to evolve.

Gene therapy in neuromuscular disorders.

Monogenic neuromuscular disorders are potentially treatable through gene therapy. Using viral vectors, a therapeutic transgene aims to restore normal levels of a protein not produced by the defective gene, or to silence a gene whose expression leads to toxic effects. Spinal Muscular Atrophy (SMA) is a good example of a monogenic disease that currently has an AAV9-based vector gene therapy as a therapeutic option. In this review, we intend to discuss the viral vectors and their mechanisms of action, in addition to reviewing the clinical trials that supported the approval of gene therapy (AVXS-101) for SMA as well as neuromuscular diseases that are potentially treatable with gene replacement therapy.