Treatment Of Spinal Muscular Atrophy Research Articles

Muscle: an independent contributor to the neuromuscular spinal muscular atrophy disease phenotype.

Spinal muscular atrophy (SMA) is a pediatric-onset neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein. SMN restorative therapies are now approved for the treatment of SMA; however, they are not curative, likely due to a combination of imperfect treatment timing, inadequate SMN augmentation, and failure to optimally target relevant organs. Here, we consider the implications of imperfect treatment administration, focusing specifically on outcomes for skeletal muscle. We examine the evidence that muscle plays a contributing role in driving neuromuscular dysfunction in SMA. Next, we discuss how SMN might regulate the health of myofibers and their progenitors. Finally, we speculate on therapeutic outcomes of failing to raise muscle SMN to healthful levels and present strategies to restore function to this tissue to ensure better treatment results.

Adeno-associated virus serotype 9 antibody seroprevalence for patients in the United States with spinal muscular atrophy

Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9 (AAV9) vector-based gene therapy for spinal muscular atrophy (SMA). Patients with elevated titers of anti-AAV9 antibodies (AAV9-Ab) should not receive onasemnogene abeparvovec because of potential safety and efficacy implications. We conducted a retrospective study to describe the seroprevalence of anti-AAV9 binding antibodies for pediatric patients with SMA in the United States. At initial testing, 13.0% (115 of 882) of patients (mean [SD] age, 26.29 [33.66] weeks) had elevated AAV9-Ab titers. The prevalence of elevated titers decreased as age increased, with 18.2% (92 of 507) of patients ≤3months old but only 1.1% (1 of 92) of patients≥21months old having elevated titers. This suggests transplacental maternal transfer of antibodies. No patterns of geographic variations in AAV9-Ab prevalence were confirmed. Elevated AAV9-Ab titers in children <6weeks old decreased in all circumstances. Lower magnitudes of elevated titers declined more rapidly than greater magnitudes. Retesting was completed at the discretion of the treating clinician, so age at testing and time between tests varied. AAV9-Ab retesting should be considered when patients have elevated titers, and elevations at a young age are not a deterrent to eventual onasemnogene abeparvovec administration. Early disease-modifying treatment for SMA leads to optimal outcomes.

Pilot Study on Newborn Screening for Spinal Muscular Atrophy.

Newborn screening (NBS) in Portugal is a significant public health measure to provide early detection for specific disorders so that early treatment is possible. Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that causes degeneration of anterior horn cells in the human spinal cord and subsequent loss of motor neurons. Its incidence is estimated in 1.6000-11.800 live births. A pilot study on 100.000 newborns is being carried out at the neonatal screening laboratory with the aim of determining the specificity, sensitivity, and feasibility of the SMA screening at the NBS laboratory in Portugal. The study presented here was based on data obtained from neonatal screening, involving the analysis of 25.000 newborns. SMA screening is performed by a qualitative detection of exon 7 of the SMN1 gene. The assay was performed using a commercially available real-time PCR, the Eonis SMN1, TREC, and KREC kit. The dried blood spots of a total of 25.000 newborns were tested; among these newborns, two were diagnosed as having SMA with survival motor neuron 1 (SMN1) deletion. These two SMA-positive samples were sent to a specialized clinical centre and a peripheral blood sample was sent to the reference laboratory for confirmation of the exon 7 deletion and determination of the SMN2 copy number. Early diagnosis and intervention are important for SMA treatment to be effective; the treatment should be started at the pre-symptomatic stage of SMA. Thus, newborn screening for SMA is strongly recommended. Currently, targeted therapies for SMA are available, and attempts are being made worldwide to include SMA screening in newborns.

Sex Difference in Spinal Muscular Atrophy Patients - are Males More Vulnerable?

Sex is a significant risk factor in many neurodegenerative disorders. A better understanding of the molecular mechanisms behind sex differences could help develop more targeted therapies that would lead to better outcomes. Untreated spinal muscular atrophy (SMA) is the leading genetic motor disorder causing infant mortality. SMA has a broad spectrum of severity ranging from prenatal death to infant mortality to normal lifespan with some disability. Scattered evidence points to a sex-specific vulnerability in SMA. However, the role of sex as a risk factor in SMA pathology and treatment has received limited attention. Systematically investigate sex differences in the incidence, symptom severity, motor function of patients with different types of SMA, and in the development of SMA1 patients. Aggregated data of SMA patients were obtained from the TREAT-NMD Global SMA Registry and the Cure SMA membership database by data enquiries. Data were analyzed and compared with publicly available standard data and data from published literature. The analysis of the aggregated results from the TREAT-NMD dataset revealed that the male/female ratio was correlated to the incidence and prevalence of SMA from different countries; and for SMA patients, more of their male family members were affected by SMA. However, there was no significant difference of sex ratio in the Cure SMA membership dataset. As quantified by the clinician severity scores, symptoms were more severe in males than females in SMA types 2 and 3b. Motor function scores measured higher in females than males in SMA types 1, 3a and 3b. The head circumference was more strongly affected in male SMA type 1 patients. The data in certain registry datasets suggest that males may be more vulnerable to SMA than females. The variability observed indicates that more investigation is necessary to fully understand the role of sex differences in SMA epidemiology, and to guide development of more targeted treatments.

Improvement of serum sample preparation and chromatographic analysis of nusinersen used for the treatment of spinal muscular atrophy

The present investigation showed that each of the three different liquid chromatography modes may be successfully used for the qualitative analysis of nusinersen metabolites in a patient's serum sample extract. However, the smallest number was detected by the hydrophilic interaction liquid chromatography. Furthermore, the response of the mass spectrometry is several times greater for ion pair chromatography compared to reversed-phase one. Various extraction methods were applied for the extraction of nusinersen metabolites from serum. Silica with bonded capture strand for hybridization was applied, as well as silica modified with amino and carboxyl groups for dispersive solid phase extraction. The hybridization allows selective extraction of nusinersen analogs, however, it fails in extraction of short metabolites. On the contrary, the efficiency of weak ion exchange-based extraction was high, even in the case of the direct extraction of nusinersen metabolites from diluted serum samples without a protein removal step. The new material is a great alternative to liquid-liquid extraction and hybridization for the isolation of nusinersen metabolites from the serum of patients with spinal muscular atrophy (SMA). It is a very simple method that uses a low concentration of organic salt and desorption occurs after changing its pH. Such complex studies were performed for the first time for nusinersen metabolites extracted from the serum of SMA patients treated with Spinraza.

Prevalence of morbidities across the lifespan for adults with spinal muscular atrophy: a retrospective cohort study

BackgroundRecently approved treatments for spinal muscular atrophy (SMA) may shift clinical care priorities to secondary complications associated with SMA-related aging. To date, there is little knowledge about the natural history of morbidities across the adult lifespan for SMA. The objective of this study was to identify the prevalence and odds ratio (OR) of various morbidities among adults with vs. without SMA prior to SMA-related treatment.MethodsThis was a retrospective cohort study that accessed Medicare fee-for-service and commercial claims data from 01/01/2008-12/22/2016. Data from adults ≥ 18 years old with SMA and without SMA matched (1:200 case:control) on demographics, region, and study entry year were included. The prevalence of 30 morbidities across physiologic systems (e.g., cardiovascular, metabolic, musculoskeletal, urinary) and mental health disorders was examined. Age- and sex-adjusted OR was estimated using logistic regression for each morbidity and effect modification by age and sex was tested.ResultsThere were 2,427 adults with SMA (mean [SD] age, 59.7 [17.4] years; 49.0% female) and 484,528 matched adults without SMA. Adults with vs. without SMA had a higher prevalence and adjusted OR of all 30 morbidities, ranging from OR = 1.61 (95% CI = 1.45–1.80) for hypothyroidism to OR = 7.80 (95% CI = 7.10–8.57) for fluid/electrolyte disorders. There was effect modification by age for 24 morbidities. The OR was highest for the youngest age group (18–40 years; OR range, 2.38 to 117.7; all P < 0.05) and declined with older age groups, but still remained significantly elevated in the oldest age group (≥ 75 years; OR range, 1.30 to 5.96; all P < 0.05).ConclusionsThe limitations of this study are that evidence of morbidities were limited to diagnostic claims and information on SMA type and symptoms or onset were not available. In conclusion, adults with SMA had a higher and earlier prevalence of a variety of morbidities across physiological systems and mental health disorders.

Evaluation of &lt;i&gt;in vitro&lt;/i&gt; functional activity of ANB4 drug for the treatment of spinal muscular atrophy

BACKGROUND: Spinal muscular atrophy (SMA) is a monogenic neurodegenerative disease. SMA is caused by a deficiency of the functional survival motor neuron protein (SMN) as a result of a mutation in the SMN1 gene. BIOCAD is developing a domestic gene therapy drug for the treatment of SMA based on recombinant adeno-associated virus serotype 9 (rAAV9) carrying the SMN1 gene (ANB4). In vitro evaluation of the functional activity of ANB4 will allow a more complete characterization of the drug.&#x0D; AIM: Development of an accurate and reproducible in vitro functional test that reflects the clinical mechanism of action of ANB4.&#x0D; METHODS: To model SMA, the SMN1 gene was knocked down by transfection with small interfering RNA. Amount of the SMN protein was measured by enzyme-linked immunosorbent assay. The functional activity of the drug was evaluated by analysis of Gemin2 protein level using the western blot analysis.&#x0D; RESULTS: Analytical method has been developed to assess the functional activity of the ANB4 drug for the treatment of SMA type 1 (rAAV9 carrying the SMN1 gene). The developed technique made it possible to obtain accurate and reproducible results. Production of Gemin2 after knockdown of SMN1 and the introduction of exogenous SMN1 gene was restored to control values, comparable with the restoration of the level of the SMN protein.&#x0D; CONCLUSION: The developed technique closely reflects the clinical mechanism of action of the ANB4 drug for the treatment of SMA. By evaluating the functional activity in vitro, accurate and reproducible results were obtained in accordance with the required standards, including the principles of 3R.

Safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 524 patients: results from an interim analysis of post-marketing surveillance in Japan

ABSTRACT Purpose Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy (SMA). A post-marketing surveillance (PMS) has been ongoing (August 2017–August 2025) in all patients in Japan who were administered nusinersen intrathecally in real-world clinical settings. We report the interim analysis results for safety and effectiveness. Methods This interim analysis was conducted using data collected from 524 patients whose case report forms were obtained at least once by May 30, 2022. Collected data included patient demographics and adverse events (AEs) for safety, and motor function assessments and Clinical Global Impressions of Improvement (CGI-I) for effectiveness. Results Of the 524 patients in the safety analysis set, 522 patients who were diagnosed with SMA were included in the effectiveness analysis (infantile-onset SMA [n = 153, 29.3%], later-onset SMA [n = 369, 70.7%]). The median duration of treatment was 785.0 (range 1–1549) days. AEs occurred in 35.9% of patients (49.0% in infantile-onset SMA and 30.6% in later-onset SMA). Nusinersen treatment significantly improved Hammersmith Infant Neurological Examination scores in patients with infantile-onset SMA and Hammersmith Functional Motor Scale-Expanded scores in patients with later-onset SMA for up to nearly 3 years. Based on CGI-I assessments, 98.5–100% of patients receiving nusinersen "improved" or remain "unchanged". Conclusions This interim analysis of the large-scale, all-case PMS in patients who were administered nusinersen in Japan supports the safety and effectiveness of nusinersen. The benefit–risk balance of nusinersen treatment remains favorable.

Efficacy of risdiplam in spinal muscular atrophy: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to assess the efficacy and safety of risdiplam on motor and respiratory function in spinal muscular atrophy (SMA). We systematically searched Medline, Scopus, Web of Science, and the Cochrane Library from inception to March 2023. We included pre-post studies that determined the effect of risdiplam on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), the 32-item Motor Function Measure (MFM32), the Revised Upper Limb Module (RULM), the Hammersmith Functional Motor Scale - Expanded (HFMSE), respiratory function, and the proportion of risdiplam-related adverse events in a population with SMA (phenotypes 1 and 2/3). Meta-analyses were also performed where possible. Eleven studies were included. After 12 months of treatment, 57% of participants with SMA1 achieved a CHOP-INTEND score ≥ 40 points, and more than half were able to feed orally and had head control. In SMA2/3, MFM32, RULM, and HFMSE increased by 2.09 (1.17, 3.01), 1.73 (1.25, 2.20), and 1.00 (0.40, 1.59) points, respectively. Efficacy on respiratory function in SMA2/3 was inconsistent. Finally, 16% of participants experienced adverse events, but serious adverse events could not be quantified due to a lack of cases. The limited available evidence suggests that risdiplam is an effective and safe drug for the treatment of SMA. In addition, long-term clinical benefit may be partly determined by the stage of disease at which treatment is initiated.

OTTM: an automated classification tool for translational drug discovery from omics data.

Omics data from clinical samples are the predominant source of target discovery and drug development. Typically, hundreds or thousands of differentially expressed genes or proteins can be identified from omics data. This scale of possibilities is overwhelming for target discovery and validation using biochemical or cellular experiments. Most of these proteins and genes have no corresponding drugs or even active compounds. Moreover, a proportion of them may have been previously reported as being relevant to the disease of interest. To facilitate translational drug discovery from omics data, we have developed a new classification tool named Omics and Text driven Translational Medicine (OTTM). This tool can markedly narrow the range of proteins or genes that merit further validation via drug availability assessment and literature mining. For the 4489 candidate proteins identified in our previous proteomics study, OTTM recommended 40 FDA-approved or clinical trial drugs. Of these, 15 are available commercially and were tested on hepatocellular carcinoma Hep-G2 cells. Two drugs-tafenoquine succinate (an FDA-approved antimalarial drug targeting CYC1) and branaplam (a Phase 3 clinical drug targeting SMN1 for the treatment of spinal muscular atrophy)-showed potent inhibitory activity against Hep-G2 cell viability, suggesting that CYC1 and SMN1 may be potential therapeutic target proteins for hepatocellular carcinoma. In summary, OTTM is an efficient classification tool that can accelerate the discovery of effective drugs and targets using thousands of candidate proteins identified from omics data. The online and local versions of OTTM are available at http://otter-simm.com/ottm.html.

Telemedicine Use, Comfort, and Perceived Effectiveness in the Spinal Muscular Atrophy Community.

Background: Telemedicine may increase access to clinical care, particularly for mobility-limited communities such as the spinal muscular atrophy (SMA) community. However, much of the information on exposure to and attitudes toward telemedicine in neuromuscular diseases generally and SMA specifically is anecdotal or from focus groups. Gaining greater insight into patient perspectives is important, given telemedicine's potential for expanding access to care and growing use of telemedicine as a result of technology advances and the COVID-19 pandemic. Methods: Cure SMA collected information on the SMA community's exposure to, comfort with, and perceived effectiveness of telemedicine through its 2021 Community Update Survey. The final analytic sample represented 463 SMA-affected individuals, resident in the United States. Descriptive analyses, correlations, and ordered logit regression models were used to characterize the sample and identify predictors of exposure, comfort, and perceived effectiveness. Data were analyzed on weighted and unweighted bases to account for differences between the survey sample and the SMA community. Stratified analyses were used to compare self-completed surveys with caregiver-completed surveys. Results: 463 individuals answered questions about telemedicine. Approximately four-fifths of these respondents had used telemedicine previously. Factors predicting greater likelihood of prior telemedicine use included male gender, increasing income, having received drug treatment for SMA, history of mental illness, and having non-neutral views regarding comfort and perceived effectiveness of telemedicine. Several factors were also significant predictors of comfort with and perceived effectiveness of telemedicine. Stratified analyses indicated differences between self-completed and caregiver-completed surveys. Conclusion: These results can provide insight into patient experiences with telemedicine and can inform approaches to its use by health care professionals and clinical trial sponsors.

Multi-omics profiling of CSF from spinal muscular atrophy type 3 patients after nusinersen treatment: a 2-year follow-up multicenter retrospective study

Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene resulting in reduced levels of the SMN protein. Nusinersen, the first antisense oligonucleotide (ASO) approved for SMA treatment, binds to the SMN2 gene, paralogue to SMN1, and mediates the translation of a functional SMN protein. Here, we used longitudinal high-resolution mass spectrometry (MS) to assess both global proteome and metabolome in cerebrospinal fluid (CSF) from ten SMA type 3 patients, with the aim of identifying novel readouts of pharmacodynamic/response to treatment and predictive markers of treatment response. Patients had a median age of 33.5 [29.5; 38.25] years, and 80% of them were ambulant at time of the enrolment, with a median HFMSE score of 37.5 [25.75; 50.75]. Untargeted CSF proteome and metabolome were measured using high-resolution MS (nLC-HRMS) on CSF samples obtained before treatment (T0) and after 2 years of follow-up (T22). A total of 26 proteins were found to be differentially expressed between T0 and T22 upon VSN normalization and LIMMA differential analysis, accounting for paired replica. Notably, key markers of the insulin-growth factor signaling pathway were upregulated after treatment together with selective modulation of key transcription regulators. Using CombiROC multimarker signature analysis, we suggest that detecting a reduction of SEMA6A and an increase of COL1A2 and GRIA4 might reflect therapeutic efficacy of nusinersen. Longitudinal metabolome profiling, analyzed with paired t-Test, showed a significant shift for some aminoacid utilization induced by treatment, whereas other metabolites were largely unchanged. Together, these data suggest perturbation upon nusinersen treatment still sustained after 22 months of follow-up and confirm the utility of CSF multi-omic profiling as pharmacodynamic biomarker for SMA type 3. Nonetheless, validation studies are needed to confirm this evidence in a larger sample size and to further dissect combined markers of response to treatment.

Spinal Muscular Atrophy: A Rare but Treatable Disease of the Nervous System

When something is rare it means that it happens very infrequently. Did you know that most diseases are rare? There are more than 6,000 known rare diseases, each affecting fewer than 1 in every 2,000 people. But if we put all the rare diseases together, they affect about 1 in 17 of us! Given that they are individually uncommon, rare diseases are often poorly understood. However, rare diseases have a large impact on families and society, thus they require increased attention. In this article, we will explore a rare disease of the nervous system called spinal muscular atrophy (SMA). We will tell you about the symptoms of SMA and explain how it is inherited. SMA has led the way in the discovery of treatments for rare diseases. Finding treatments for rare diseases requires intensive research and commitment from many people, but the success of SMA treatments highlights the importance of studying other rare conditions.

Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment.

Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, SMN1, was identified. Genetic testing of SMN1 has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for SMN1 deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, SMN1-deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA.

Patients with Spinal Muscular Atrophy Type 1 Achieve and Maintain Bulbar Function Following Onasemnogene Abeparvovec Treatment.

Improvement and maintenance of bulbar function are goals of disease-modifying treatments for spinal muscular atrophy (SMA). Lack of standardized measures and a widely accepted definition of bulbar function represents a gap in SMA care. A multidisciplinary team conducted post-hoc analyses of pooled data from one phase 1 (START) and two phase 3 (STR1VE-US, STR1VE-EU) studies to define and evaluate bulbar function of infants with SMA type 1 after receiving one-time gene replacement therapy, onasemnogene abeparvovec. We defined bulbar function as the ability to meet nutritional needs while maintaining airway protection and the ability to communicate verbally. Four endpoints represented adequate bulbar function: (1) absence of clinician-identified physiologic swallowing impairment, (2) receiving full oral nutrition, (3) absence of adverse events indicating pulmonary instability, and (4) the ability to vocalize at least two different, distinct vowel sounds. We descriptively assessed numbers/percentages of patients who achieved each endpoint and all four collectively. Patients were followed until 18 months old (STR1VE-US and STR1VE-EU) or 24 months (START) post-infusion. Overall, 65 patients were analyzed for swallowing, nutrition intake, and adverse events, and 20 were analyzed for communication. At study end, 92% (60/65) of patients had a normal swallow, 75% (49/65) achieved full oral nutrition, 92% (60/65) had no evidence of pulmonary instability, 95% (19/20) met the communication endpoint, and 75% (15/20) achieved all four bulbar function components in the composite endpoint. In these three clinical trials, patients with SMA type 1 who received onasemnogene abeparvovec achieved and maintained the bulbar function criteria utilized within this investigation.

Consensus on Gene Replacement Therapy for the Treatment for Spinal Muscular Atrophy

Consensus on Gene Replacement Therapy for the Treatment for Spinal Muscular Atrophy

Effects of the COVID-19 Pandemic on SMA Screening and Care: Physician and Community Insights.

As part of efforts to reduce diagnostic delays and enhance clinical trials, Cure SMA evaluated the effects of COVID-19 on SMA care and clinical trial conduct. Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive, potentially debilitating muscle weakness and atrophy. Uninterrupted access to early diagnosis, disease-modifying treatment, and care for SMA is vital to avoiding irreversible motor neuron death and achieving optimal patient outcomes. Two surveys were conducted: a provider survey and a community survey. The Provider Impact Survey, distributed from November 24, 2020, through March 8, 2021, assessed COVID-19's effects on referrals for evaluation of suspected SMA, cancellations and delays of SMA-related care, and clinical trials. The Community Impact Survey was fielded in three waves between April 7, 2020 and July 19, 2021, in tandem with Cure SMA COVID-19 support programs. A total of 48 completed provider surveys (22 from care sites, 26 from care-and-trial sites) reflected decreases in referrals for suspected SMA, increases in appointment cancellations and delays, and patient reluctance to attend in-person visits due to COVID-19. One-third of care-and-trial sites reported trial recruitment delays, and one-quarter reported pausing trial enrollment. Results of the Community Impact Survey, completed by 2047 individuals, showed similar disruptions, with 55% reporting changes or limitations in accessing essential SMA-related services. This research evaluates the pandemic's interruption of SMA care and research. These insights can help mitigate and increase preparedness for future disruptive events. Expanded use of virtual tools including telehealth and remote monitoring may enhance continuity and access. However, additional research is required to evaluate their effectiveness. While this research was specific to SMA, its findings may have relevance for other patient communities.

Rehabilitation in Spinal Muscular Atrophy; A Narrative Review

Spinal muscular atrophy (SMA) is a group of genetic diseases that cause muscle weakness and mobility problems. There are no clear clinical guidelines for assessing and rehabilitating individuals with SMA, despite its increasing prevalence. This study aimed to provide a comprehensive review of physical therapy's effectiveness in improving treatment outcomes for SMA by analyzing existing literature. A search was conducted in Pubmed, PEDro and Google scholar using relevant keywords. Studies on assessment, treatment, and rehabilitation for SMA were included in the review. The review found that assessment must be comprehensive, and rehabilitation approaches include exercise training, positioning, orthotics, and mobility aids, chest physiotherapy, contracture and scoliosis management, and aquatic exercises. Physical therapy improves the quality of life for children with SMA at every stage of the disease. However, there is still insufficient evidence on the effectiveness of physical therapy in managing people with SMA, and more high-quality studies are needed.

Spinal muscular atrophy – the effectiveness of treatment and new therapeutic possibilities for selected groups of patients in Poland

Spinal muscular atrophy (SMA) is a rare hereditary neuromuscular disorder caused by a genetic mutation in the Survival of motor neuron 1 (SMN1) gene, which is responsible for the production of a protein essential to motor neurons’ survival. Insufficient levels of the SMN protein lead to the loss of motor neurons in the spinal cord, which manifests in progressive muscle wasting. Due to the absence of an effective treatment in the early years, the disease was taking its toll with the respiratory problems being the primary cause of death. Currently, there are multiple approved treatments for SMA, which help to manage the symptoms and to prevent complications, such as nusinersen, risdiplam, and onasemnogene abeparovec. In Poland, nusinersen treatment has been offered free of charge by the public health service since 2019. It wasn’t until September 2022 that the reimbursement procedure included the other two drugs. The recently published studies on the nusinersen treatment in Poland showed stabilization or slowdown in the progression of symptoms in all patients. In March 2022, Poland implemented an SMA screening program for newborns, which aimed to detect this fatal and disabling disease before the infant displayed any SMA symptoms. The program resulted so far in early diagnosis and intervention providing a better prognosis for patients. Combination of newborn screening and the drug reimbursement program has significantly increased the chances of SMA patients for effective treatment.

Splicing activates transcription from weak promoters upstream of alternative exons

Transcription and splicing are intrinsically coupled. Alternative splicing of internal exons can fine-tune gene expression through a recently described phenomenon called exon-mediated activation of transcription starts (EMATS). However, the association of this phenomenon with human diseases remains unknown. Here, we develop a strategy to activate gene expression through EMATS and demonstrate its potential for treatment of genetic diseases caused by loss of expression of essential genes. We first identified a catalog of human EMATS genes and provide a list of their pathological variants. To test if EMATS can be used to activate gene expression, we constructed stable cell lines expressing a splicing reporter based on the alternative splicing of motor neuron 2 (SMN2) gene. Using small molecules and antisense oligonucleotides (ASOs) currently used for treatment of spinal muscular atrophy, we demonstrated that increase of inclusion of alternative exons can trigger an activation of gene expression up to 45-fold by enhancing transcription in EMATS-like genes. We observed the strongest effects in genes under the regulation of weak human promoters located proximal to highly included skipped exons.