Current evidence for treatment with nusinersen for spinal muscular atrophy : a systematic review

Recent discovery of nusinersen, an antisense oligonucleotide drug, has provided encouragement for improving treatment of spinal muscular atrophy. No therapeutic options currently exist for this autosomal recessive motor neuron disorder. Nusinersen is developed for intrathecal use and binds to a specific sequence within the survival motor neuron 2 pre-messenger RNA, modifying the splicing process to promote expression of full-length survival motor neuron protein. We performed a MEDLINE and CENTRAL search to investigate the current evidence for treatment with nusinersen in patients with spinal muscular atrophy. Four papers were withheld, including two phase-3 randomized controlled trials, one phase-2 open-label clinical trial and one phase-1 open-label clinical trial. Outcome measures concerned improvement in motor function and milestones, as well as event-free survival and survival. Results of these trials are hopeful with significant and clinically meaningful improvement due to treatment with intrathecal nusinersen in patients with early- and later-onset spinal muscular atrophy, although this does not restore age-appropriate function. Intrathecal nusinersen has acceptable safety and tolerability. Further trials regarding long-term effects and safety aspects as well as trials including broader spinal muscular atrophy and age categories are required and ongoing

Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity. To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number. A working group comprised of 15 SMA experts participated in a modified Delphi process, moderated by a neutral third-party expert, to develop treatment guidelines. The overarching recommendation is that all infants with two or three copies of SMN2 should receive immediate treatment (n = 13). For those infants in which immediate treatment is not recommended, guidelines were developed that outline the timing and appropriate screens and tests to be used to determine the timing of treatment initiation. The identification SMA affected infants via newborn screening presents an unprecedented opportunity for achievement of maximal therapeutic benefit through the administration of treatment pre-symptomatically. The recommendations provided here are intended to help formulate treatment guidelines for infants who test positive during the newborn screening process

Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector) be sensibly selected, but considerable thought must be applied to the where, which, what, and when in order to enhance treatment benefit: to where (cell types and tissues) must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments

Nusinersen en el tratamiento de la atrofia muscular espinal: experiencia en Pediatría del Hospital Universitario Río Hortega

La atrofia muscular espinal (AME) es una enfermedad neurodegenerativa que conlleva una pérdida de fuerza progresiva e hipotonía. Se trata de una enfermedad genética debida a mutaciones en el gen SMN1, lo que ocasiona un déficit de la proteína de supervivencia de motoneuronas (SMN). El gen SMN2 suple parcialmente la función del gen dañado; en función del número de copias de dicho gen existen diferentes formas clínicas, más o menos severas. La AME es una enfermedad discapacitante, y mortal en sus formas más severas. Hasta el momento únicamente se ha podido ofrecer tratamiento sintomático, pero en 2016 se inició el uso clínico de nusinersen (Spinraza®), un oligonucleótido antisentido de administración intratecal que logra aumentar la cantidad de proteína SMN funcionante, tratando la enfermedad desde su base molecular. En mayo de 2018 se administró por primera vez en nuestra Comunidad Autónoma, en el Hospital Universitario Río Hortega (HURH), y en un año se han administrado un total de 34 dosis a pacientes pediátricos. Durante este tiempo han sido tratados en pediatría del HURH seis pacientes; uno de ellos ha fallecido, y el resto han estabilizado su enfermedad y no han mostrado efectos secundarios derivados del tratamiento. Aún es demasiado pronto para sacar conclusiones a largo plazo, pero la situación es esperanzadora para esta enfermedad, aunque también se plantean importantes retos en relación a los costes y resultadosGrado en Medicin

Clinical impact of splicing in neurodevelopmental disorders.

Clinical exome sequencing is frequently used to identify gene-disrupting variants in individuals with neurodevelopmental disorders. While splice-disrupting variants are known to contribute to these disorders, clinical interpretation of cryptic splice variants outside of the canonical splice site has been challenging. Here, we discuss papers that improve such detection

Gene suppression approaches to neurodegeneration

Gene suppression approaches have emerged over the last 20 years as a novel therapeutic approach for the treatment of neurodegenerative diseases. These include RNA interference and anti-sense oligonucleotides, both of which act at the post-transcriptional level, and genome-editing techniques, which aim to repair the responsible mutant gene. All serve to inhibit the expression of disease-causing proteins, leading to the potential prevention or even reversal of the disease phenotype. In this review we summarise the main developments in gene suppression strategies, using examples from Huntington’s disease and other inherited causes of neurodegeneration, and explore how these might illuminate a path to tackle other proteinopathy-associated dementias in the future

Newborn genetic screening for spinal muscular atrophy in the UK : the views of the general population

Background: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and a leading genetic cause of infant death worldwide. However, there is no routinescreening programme for SMA in the UK. Lack of treatments, and the inability of the screening test to accurately predict disease severity are among the key reasons screening programmes have faltered in the UK. With the recent release of the first therapy for SMA (Nusinersen) calls are being made for a reconsideration of this stance, however very little is known about the views of the general public. Methods: An online survey was administered to 232 individuals with no prior relationship to SMA to assess their attitudes towards a newborn screening programme for it. Results were compared with previously gathered data on the views of SMA families. Results: 84% of participants were in favour of newborn screening. Key reasons for support were a belief that it would lead to better healthcare and life expectancy for affected infants and facilitate informed decision-making for future pregnancies. Key reasons for non-support were a belief in the potential for significant negative impact on the family in terms of bonding and stress. Conclusions: Public acceptability is a key component in the evaluation of any potential screening programme in the UK. This study demonstrates that newborn screening for SMA is viewed largely positively by people unfamiliar with the condition. Indeed, a belief in the centrality of early identification overrode all other social and ethical concerns about screening, for the majority of participants

Newborn screening for spinal muscular atrophy : the views of affected families and adults

Spinal muscular atrophy (SMA) is one of the leading genetic causes of infant death worldwide. However, due to a lack of treatments, SMA has historically fallen short of Wilson-Jungner criteria. While studies have explored the acceptability of expanded newborn screening to the general public, the views of affected families have largely been overlooked. This is in spite of the potential for direct impacts on them and their unique positioning to consider the value of early diagnosis. We have previously reported data on attitudes towards pre-conception and prenatal genetic screening for SMA amongst affected families (adults with SMA (n=82) and family members (n=255)). Here, using qualitative interview (n= 36) and survey data (n= 337), we report the views of this same cohort towards newborn screening. The majority (70%) of participants were in favour, however, all sub-groups (except adults with type II) preferred pre-conception and/or prenatal screening to newborn screening. Key reasons for newborn screening support were: 1) the potential for improved support 2) the possibility of enrolling pre-symptomatic children on clinical trials. Key reasons for non-support were: 1) concerns about impact on the early experiences of the family 2) inability to treat. Importantly, participants did not view the potential for inaccurate typing as a significant obstacle to the launch of a population-wide screening programme. This study underscores the need to include families affected by genetic diseases within consultations on screening. This is particularly important for conditions such as SMA which challenge traditional screening criteria, and for which new therapeutics are emerging