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The Institute for Clinical and Economic Review (ICER) will compare the clinical effectiveness and value of the only approved disease-modifying treatment for spinal muscular atrophy (SMA) —  Spinraza (nusinersen, by Biogen) — and an investigational gene therapy showing promise in advanced clinical trials — Novartis‘ AVXS-101,…

Researchers at Mizzou — the University of Missouri — have started a new company, Shift Pharmaceuticals, to test the clinical effectiveness of a molecule that may help improve the outcomes of people with spinal muscular atrophy (SMA). SMA develops due to mutations in the survival motor neuron-1…

A newly identified mutation in the DYNC1H1 gene causes a rare form of spinal muscular atrophy known as SMA with lower limb predominance (SMA-LED), which is associated with learning difficulties and brain malformations, according to a…

The degree of motor skills, and the intensity of feelings of depression and fatigue influence the degree to which adults with spinal muscular atrophy (SMA), regardless of subtype, participate in and enjoy the social and professional activities of daily life, a study from the Netherlands reports. The study, “…

A physiotherapy program that alternates whole-body vibration with intensive rehabilitation shows potential to improve motor function and mobility scores in children with SMA type 2 and 3, a study reports. The program combines in-patient neuromuscular interval rehabilitation with home-based whole-body vibration to address the progressive loss of muscle strength caused by SMA. Studies in both SMA patients and animal disease models suggest that targeted exercise may improve muscular strength and motor function. Research focusing specifically on whole-body vibration has also shown a potential to improve neuromuscular function in children. This technique induces reflex-based muscle contractions, producing involuntary muscle contractions and providing positive feedback mechanisms that strengthen muscles.  Whole-body vibration is also thought to be faster and safer than regular exercises alone. The program was tested in an observational study at University Hospital Cologne, Germany, involving 38 SMA children (mean age, 4.64). It was composed of two inpatient stays — the first for 13 days of inpatient training, then three months of at-home training, followed by a second six-day inpatient stay. Finally, patients had six months of home rehabilitation before  final assessment of improvements. The in-patient stay involved four-to-five hours of daily goal-oriented physiotherapy, with or without the whole-body vibration apparatus. During this time, families and caregivers were trained on using the vibration apparatus at home. During home training, a side-alternating whole body vibration device was used with standard exercises, such as standing, sitting, and the 4-point position. Vibrations were applied through a vibrating surface that mechanically stimulates the child on its platform, and induces reflex-based muscle contractions. Each whole-body vibration session takes about three minutes and are repeated three times. Children were  assessed for changes in motor function using the Gross Motor Function Measure (for those assessed before 2011) or the Hammersmith Functional Mobility Scale (for post-2011 assessments).  In total, 14 children were available for full evaluation — made at the beginning, after six months of home-based training, and after six months of follow-up — using the Gross Motor Function Measure, and 11 using the later measure, the Hammersmith Functional Mobility Scale. Hammersmith is a scale of 20 activities that is specifically designed for SMA type 2 and 3; the Gross Motor Function was designed for children with cerebral palsy, but has been applied to other diseases. Data showed that whole-body vibration assisted training improved both motor function and mobility, with further benefits seen after the intensive training period. Eight of 11 children (72.7%) had a more than two-point improvement in the Hammersmith Functional Mobility Scale score, while the other four showed an increase between 0 and 2 points. These point increases, the researchers noted, were significantly higher than what would be expected based on natural improvement over time (10%). Somewhat similar improvements in muscular strength and function were also seen in six of 13 children assessed under the Gross Motor Function Measure — but the study did not detail these at length.

Spotlight Innovation announced that the nonprofit Cure SMA has awarded $300,000 to Prof. Kevin Hodgetts, of Brigham and Women’s Hospital in Boston and a Spotlight research collaborator, for the preclinical development of the potential therapy LDN-5178 for spinal muscular atrophy. Hodgetts' project is titled "Pre-Clinical Development of LDN-5178 for the Treatment of SMA." Spotlight Innovation is a pharmaceutical company that licensed the worldwide development and commercialization rights for LDN-5178 from the Indiana University Innovation and Commercialization Office. Individuals with two faulty copies of the survival motor neuron 1 gene will develop SMA. The SMN protein that is normally encoded by the SMN1 gene is involved in the function of nerve cells that carry signals from the brain to move certain muscles. Although our bodies have another gene that produces SMN, the SMN2 gene — often called the SMA backup gene — it is not enough to make up for the loss of normal SMN1 gene function in individuals with SMA. The grant awarded to Hodgetts will be applied to the study of small molecules that can increase the amount of accumulated SMA protein produced by SMN2 to compensate for the loss of SMN1. This is expected to result in increased SMN protein in the brain and normalize the function of nerve cells that are affected in SMA. Hodgetts and his team have previously "identified lead compounds that increased SMN protein in brain and extended survival and motor function in a mouse model of SMA," Hodgetts said in an interview with Cure SMA. He said the SMA grant will help the teams to "continue the development of ... lead series of compounds, performing preclinical drug properties and toxicity studies, to ensure that they are as safe and effective as possible prior to entering clinical trials." The research funded by the grant will be carried out by Hodgetts and his team at the Laboratory for Drug Discovery in Neurodegeneration at Brigham and Women’s Hospital, an affiliate of Harvard Medical School, and Prof. Elliot Androphy and his team at Indiana University.

Either by coincidence or by design, MDA Hellas, the Muscular Dystrophy Association of Greece, is located on Elpidos Street in downtown Athens. Elpidos is Greek for “hope” — and that’s exactly what MDA Hellas offers the many neuromuscular disease patients under its care. Antigone Karras, executive manager of the…

Motor neuron death in patients with spinal muscular atrophy is related to abnormal RNA editing of two specific proteins, which leads to the activation of a key cell death pathway and neurodegeneration, a study suggests. Genes, which are composed of DNA sequences, are transcribed into molecules called RNA. In turn, RNA molecules are used as templates to make proteins, which carry out various functions in a cell. SMA is a neurodegenerative disease characterized by widespread RNA dysfunction, leading to the abnormal production of various proteins. RNA dysfunction in SMA patients is the result of a mutation in the gene that provides instructions to make the survival motor neuron protein, which is a major regulator of RNA splicing. RNA splicing is a process by which RNA molecules are edited to produce the final RNA product. When an RNA molecule is initially made, it is composed of alternating regions known as exons or introns. Through the use of RNA splicing, the intros of the RNA molecules are cut out and the exons are joined together. These exons are a vital part of the RNA molecule that actually contain the instructions used to make the protein. A deficiency in SMN leads to significant RNA dysfunction. One of the hallmarks of SMA is the progressive loss of spinal motor neurons, and researchers have been trying to understand the cause behind the excessive death of these motor neurons in patients. Studies using mouse models of SMA have shown that motor neuron death can be attributed to the p53-dependent pathway, which is activated by high levels of a protein called p53. The role of p53 in cells is to stop them from dividing and trigger the pathways that result in cell death. The molecular mechanisms that link a deficiency in the SMN protein to p53 activation and motor neuron death in SMA are currently unknown. Normally, p53 expression is kept at low levels in the cell by Mdm2 and Mdm4, proteins that negatively regulate p53. Therefore, researchers hypothesized that p53 activation in SMA involves a dysregulation of Mdm2 and Mdm4 due to abnormal RNA splicing caused by an SMN deficiency. Using both cellular and animal models, researchers in this study showed that a deficiency in the SMN protein “disrupts the balance between inclusion and exclusion of key regulatory exons in Mdm2 and Mdm4.” Specifically, they observed that exon 3 of Mdm2 and exon 7 of Mdm4 are not included in the final RNA molecules for these proteins in SMN-deficient cells. This dysfunction in RNA splicing activity causes problems in the biological activity of Mdm2 and Mdm4, and p53 becomes active. In fact, prior studies have shown that irregular RNA splicing of these specific exons is associated with an increase in p53 activity. Therefore, researchers conclude that their findings mechanistically link dysregulation of alternative splicing induced by SMN deficiency with motor neuron death, the key hallmark of SMA.

Young children with spinal muscular atrophy show improvements in motor function after six-months of treatment with Spinraza, a German study shows. The response to Spinraza strongly correlated with the age when treatment began, with children treated before seven months of age responding better to the therapy. These findings support the need for early detection of SMA by screening newborns, study authors emphasized. Spinraza, developed by Biogen, is the first FDA-approved drug for SMA. SMA arises due to mutations in the survival motor neuron 1 (SMN1) gene, which is key to the function and survival of the nerves that control muscles. Some patients, however, maintain a copy of a gene called SMN2, a gene nearly identical to SMN1 that can give rise to a shorter version of the SMN protein. Spinraza boosts the amount of the SMN protein by increasing the levels of full-length messenger RNA (mRNA), the mediator between gene and protein, generated by the SMN2 gene. Spinraza is administered via intrathecal injection — directly to the cerebrospinal fluid around the spinal cord, where motor neurons of SMA individuals degenerate due to insufficient levels of SMN protein. The therapy was approved in the U.S. in December 2016 to treat SMA types 1–3 in children and adults, and learned approval in Europe in June 2017. Prior to the EU’s approval, a group of children in Germany with SMA type 1 was given access to Spinraza for seven months, under an Expanded Access Program (EAP). The children had different ages and were at different stages of the disease, representing a more heterogenous group than those in previous trials. Researchers analyzed data from 61 children treated with Spinraza in seven centers under the EAP. Children enrolled in the study developed the first symptoms of SMA before the age of 6 months and had no ability to sit independently. Moreover, 38 children had less than two copies of the SMN2 gene, and 20 children had more than three copies. In three children, the SMN2 copy number was unknown. Previous studies showed that a higher number of SMN2 correlates with longer survival and inversely with disease severity. Administration of Spinraza was performed on days 1, 15, 30, 60 and 180. Researchers measured the treatment outcomes by assessing primarily the changes from the beginning of the study in the score of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, also known as (CHOP INTEND), which measures motor function. The CHOP-INTEND scores range from 0 to 64 points and previous studies have reported that children with SMA type 1 have a mean value of 21.4 points. The test was performed at the beginning of the study, then after 60 days, and at the end of treatment. Additionally, they assessed changes in scores in section 2 of the Hammersmith Infant Neurological Examination (HINE) scale, another test measuring motor function, whose scores range between zero and 26. The HINE-2 was performed routinely at every patient visit. At baseline, children’s mean CHOP INTEND score was 22.3 and after six months of treatment the mean score improved to 31.2, which was an increase of nine points. Specifically, eight children improved by one to four points, and 17 children improved by five to nine points. Sixteen children improved by more than 10 points (between 10 and 14 points), and 11 children underwent an increase on the CHOP INTEND by more than 15 points. Children with less than two copies of the SMN2 gene had lower scores in the CHOP INTEND at the beginning of the trial. The changes in scores after treatment were comparable to children with more than three SMN2 copies, scores of 8.1 and 8.2, respectively. Treatment was more effective in younger children (aged below 7 months) compared to older ones — an improvement of 14.4 vs. 7.0, respectively. These results suggest there is a “critical therapeutic time window for delivery of SMN-targeted therapies. The implementation of newborn screening for SMA is crucial to allow pre-symptomatic diagnosis." Regarding the motor response, 19 children improved by more than two points in HINE-2 motor milestones —  15 children increased their score by two to four points, and four children by more than five points. Four children (6.6%) achieved full head control, and 2 children (3.3%) were able to sit independently. After six months of treatment, the parents of 28 children reported a marked improvement in motor function, while three parents noticed no benefit, and one a slight worsening. Respiratory function was improved in 16 children, with a marked improvement in four of them. Overall, these findings “indicate that even in advanced stages of the disease, Spinraza can lead to improvement of motor function as measured by CHOP INTEND. Moreover, the results support early diagnosis and access to Spinraza as early as possible as a key factor to improve the outcomes of children with SMA. Researchers now will evaluate whether increasing the treatment period with Spinraza enhances the therapy’s benefits and patients' quality of life. The data will be collected within the SMArtCARE project, a “real-world data” registry of SMA patients.

Spinal muscular atrophy (SMA) patients can be more prone to a life-threatening metabolic imbalance called ketoacidosis, which causes the blood to become acidic, a case report highlights. In patients with neuromuscular diseases like SMA, physicians should be particularly suspicious of this complication so that…