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The paper provides a short history of spinal muscular atrophy.
The paper highlights the new challenges related to the new therapies
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We report new issues in the classification of spinal muscular atrophy.
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New phenotypes, assessments and care recommendations are also reported.
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Results in presymptomatic patients highlight the need for neonatal screening.
Abstract
The aim of this paper is to provide a short history of spinal muscular atrophy, from the first descriptions of the disease to the impact of the most recent therapeutical advances on the disease course. The paper provides an overview of how the field has progressed over the years after the availability of care recommendations and, more recently of the new therapies. The paper also highlights the new challenges related to the interpretation of the efficacy of the new therapies and how these are likely to affect several aspects such as the classification of spinal muscular atrophy. We will also discuss the need for further work to better define possible new phenotypes and new methods of assessments and how these should be reflected in the care recommendations. The results in presymptomatic patients will finally highlight the need for neonatal screening.
1. Introduction
The recent advent of new therapeutical approaches in spinal muscular atrophy (SMA) is the crowning achievement of a long journey started over a century ago when the disease was first reported (Fig. 1). The first descriptions of spinal muscular atrophy dates to the last decade of the 19th century. In 1891 Guido Werdnig reported two brothers with weakness in whom degeneration of the anterior horn cells was found on autopsy [
]. In the following years other papers have provided further clinical details and the description of the typical phenotype characterized by jug handle posture of the arms, intercostal weakness and sparing of the diaphragm and no facial weakness.
SMA, spinal muscular atrophy; SMN, survival of motor neuron.
a Werdnig G. Arch Psychiatr Nervenkr. 1891; 22:437480; b Hoffmann J. Deut Zeitsch Nervenheilkd 1893; 3:427470; c Kugelberg E & Welander L. AMA Arch Neurol Psychiatry 1956; 75:500509; d Dubowitz, V. Brain 1964;87:707-18; e Munsat TL, et al. Neuromuscul Disord 1992; 2:423428; f Brzustowicz LM, et al. Nature 1990 Apr 5;344:540-1.; Melki J, et al. Nature 1990;344:767-8.g Lefebvre S, et al. Cell 1995; 80:155165. h Frugier T, et al. Hum Mol Genet. 2000; 9:849858; Hsieh-Li HM, et al. Nat Genet 2000; 24:6670; I MacLeod MJ et al. Eur J Paediatr Neurol 1999;3:65-72. j Wang CH, et al. J Child Neurol. 2007; 22:102710497; k Mercuri E, et al. Neurology 2007; 68:5155; l Biogen Inc. SPINRAZATM (nusinersen) US prescribing information. m Dominguez E, et al. Hum Mol Genet 2011;20:681693; Foust KD, et al. Nat Biotechnol 2010; 28:271274; Passini MA, et al. J Clin Invest 2010; 120:12531264; n Chiriboga CA, et al. Neurology 2016;86:890-7.Finkel RS, et al. Lancet 2016;388:3017-26. Finkel RS, et al. N Engl J Med 2017;377:1723-32. Mercuri E et al. N Engl J Med 2018;378:625-35; o Naryshkin NA, et al. Science 2014. 345:688693;p Mercuri E, et al. Neuromuscul Disord 2018; 28:103115. Finkel et al. Neuromuscul Disord 2018; 28:1116125; q Mendell JR, et al. N Engl J Med 2017; 377: 171322. Day JW et al. Lancet Neurol 2021;20:284-293.; Mercuri E et al. Lancet Neurol, in press; r Baranello G, et al. N Engl J Med 2021;384:915-23. Darras B N Engl J Med 2021;385(5):427-435.
After almost five decades, another form of hereditary motoneuron involvement with less severe phenotypes were described. Kugelberg and Welander reported a milder form, compatible with ambulation [
], in whom proximal weakness and neurogenic signs on neurophysiology and muscle biopsy were consistent with motoneuron involvement and were labelled as a mild variant of Werdnig Hoffmann disease. A few other studies have reported both severe and milder phenotypes these findings suggesting a wider spectrum of clinical findings than the one originally reported [
] written a few years ago by Victor Dubowitz, another important name in the SMA journey whose contribution to identify and better characterize the different forms of the disease is universally known. In 1964 Dubowitz reported a series of 12 cases with ‘almost non progressive’ form of neurogenic muscular atrophy with onset in infancy and longer survival than in the infantile form described by Werdnig and Hoffmann [
]. These findings provide the first systematic description of the ‘intermediate’ form as a new phenotype, with onset in infancy but associated with a slow progression.
Other important steps were the discovery of the location of the gene for spinal muscular atrophy on chromosome 5 in 1990 [
], that allowed to confirm that the three known different phenotypes, ranging from severe to mild, were allelic forms related to mutations in the same gene rather than 3 genetically different diseases [
] proposed a classification that was a compromise between a numerical approach (type 1, 2 and 3), mainly based on age at onset and survival, and another approach based on severity (severe, intermediate and mild) and on the ability to achieve important motor milestones (sitting, standing/walking).
This classification has proved to be very useful over the years but still did not take into account the large variability that can occur within each type. Over the years there have been several attempts to add further criteria to reduce the intra-type variability. The most used approach is the decimal subclassification proposed by Dubowitz that allows to identify patients with different severity within each type (1.1 to 1.9 for type 1, 2.1 to 2.9 for type 2 an 3–1 to 3.9 for type 3) [
. Type 1a includes infants with neonatal onset, type 1b infants with onset after the first month who do not achieve head control and 1c including those who generally have onset of signs after 3 months and generally achieve head control. This classification is mainly based on age at onset of clinical signs and is often, but not always, associated with the overall severity that is better characterized in the decimal classification [
Hausmanowa-Petrusewicz I. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients.
The possibility to test for mutations in the SMN1 gene in patients with less common phenotypes has allowed to identify a new phenotype, with prenatal onset, absent or extremely reduced fetal movements, contractures and severe motor and respiratory involvement at birth, that has been labelled as Type 0 [
. There is still debate whether, at the end of the spectrum, the forms with late adult onset and a mild phenotype should be labelled as type 4 or whether this should be considered as the mild end of the spectrum of type 3.
The whole classification system is however currently under debate. With neonatal screening and the possibility to treat infants before the onset of clinical signs, it will be difficult to use the traditional criteria for classification as both onset and severity are being affected by the new treatments. Because of this there is a suggestion to identify presymptomatic patients according to the SMN2 copy number but there is no consensus because, although there is an overall correlation between copy number and severity, this does not always apply to individual cases [
Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.
Even before the advent of therapeutic approaches, survival and disease progression had already changed following the introduction of standardized care recommendations, originally published in 2007 [
Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics.
. The revised recommendations include different topics: Diagnosis and genetics, Physical therapy and rehabilitation, Orthopedic care, growth and bone health care; Nutrition, Pulmonary care, Ethics and palliative care, Acute care, Other organ system involvement, Medication.
The recommendations highlight the need to have regular and reliable assessments as part of the clinical routine and provides details of the type and frequency of intervention in the different areas. Particular attention was devoted to the new information on management of scoliosis, with recommendation for earlier surgical treatment of spine deformity with new techniques.
A new section on Acute Care was added to introduce the need for setting home and local hospital care including individualized anticipatory care plans, criteria for presentation to emergency care, and instructions to be shared with community first responders.
3. New therapies
In the last few years the field of SMA has completely changed. Three therapies have so far been approved, all targeting an increase in the production of SMN protein. This can be achieved going to the root of the genetic defect, with gene replacement of the defective SMN1 gene [
Viral gene therapy has been possible because of the small size of SMN1 that is compatible with the use of adeno-associated viral vectors (AAV9) as a vector [
]. A phase I clinical trial using a single intravenous delivery of Onasemnogene Abeparvovec in infants with SMA-I (START, NCT02122952) showed clear signs of efficacy, both in term of survival and improved motor function, with a good safety profile [
. The administration was well tolerated with some cases of elevated serum aminotransferase levels that could be controlled by prednisolone administration. These results led to FDA approval in 2019, for infants with SMA. These results were followed by two larger open-label multicentre phase III studies in the US [STR1VE US, NCT03306277] [
Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
are now commercially available. The first to be approved was Nusinersen, an antisense oligonucleotide. Two successful randomised double blind controlled clinical trials performed in infants under 7 months of age with SMA-I (ENDEAR, [
]) led to the approval of Nusinersen in 2016 by the FDA, followed by European Medicines Agency (EMA) and several other countries worldwide. There are now over 11,000 patients treated with Nusinersen worldwide. There is a rapidly increasing number reporting efficacy of the drug in a real world setting. While most of the early real-world data focused on type 1 infants enrolled in early access programs, [
Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
] covering the whole spectrum of SMA, from young infants with the severe neonatal onset forms to adults with milder phenotypes. The real-world data have expanded our knowledge on safety and efficacy of the drug in a much larger population of SMA patients than those reported in the pivotal studies.
The other approach targeting to modify SMN2 exon 7 splicing and regulating SMN2 exon 7 inclusion, implies the use of small molecules. One of them, risdiplam, has completed randomized, placebo-controlled studies in both early onset type I patients (FIREFISH, NCT02913482)[31], and in children and young adults with later-onset SMA (SUNFISH, NCT02908685), therefore including also patients older than 12 years that had not been included in previous studies. The results of the trials showed a significant improvement in survival I type 1 infants and improved motor function with an excellent safety profile. One of the advantages of using a small molecule is that they are able to cross the blood brain barrier and may therefore have also a CNS and a peripheral effect [
The drug is now becoming available in most countries after approval or for compassionate use and
The results of the three clinical trials studies performed in infants in the first 6–7 months of age have clearly demonstrated that in symptomatic type 1 infants the dramatic increase in survival is associated with a functional improvement that is better seen in infants treated in the first months, who often achieve the ability to sit, never achieved before treatments became available. The long term results of the trials confirm that the efficacy is sustained over time [
Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
. The first published results of the real world usage of Nusinersen, mainly focused on SMA-I patients but with a much wider spectrum of age than those enrolled in the ENDEAR study, confirmed that the best results were found in the younger patients treated before 6 months but significant motor function improvements could also be found in infants treated between 7 and 24 months [
, and there is a rapidly increasing number of studies reporting the use of nusinersen in type 2 and 3 patients of all ages showing concordant positive changes on all the functional measures explored, at difference with the natural history studies consistently showing negative changes. These accumulating data indicate that nusinersen appears to have a favorable response in motor function across the spectrum of age and severity of disease and that the expectations from treatment in an individual patient need to be adjusted accordingly. Real world data are currently being collected also for Onasemnogene abeparvovec [
] and risdiplam, that have recently become available.
Other studies are exploring other mechanisms, such as those using fast skeletal muscle troponin activators or targeting myostatin, a potent negative regulator of skeletal muscle growth [
]. A study exploring the effect of SRK-015, a fully human anti-pro-Myostatin monoclonal antibody in patients with and without treatment with Nusinersen has shown promising preliminary results (NCT03921528).
4. New challenges
The new therapies are a great achievement for the SMA patients but in a way also represent the beginning of a new era that will face several challenges to better understand the level of response and safety of the different drugs, alone or in combination, and of long term results and new phenotypes.
Combinatorial studies with the existing available drugs are now being designed. Ongoing studies are collecting data from patients who may wish to switch from an existing treatment to another, such as the Jewelfish study proposing Risdiplam to patients previously exposed to Nusinersen or AVXS-101. (NCT03032172) or the RESTORE study targeting patients exposed to onasemnogene abeparvovec who will ‘add’ Nusinersen. The SRK-015 anti-myostatin study, previously described, also includes patients who will add the new compound to an existing treatment with nusinersen.
Increasing attention has been devoted to treating presymptomatic patients. The results of a completed phase II, open-label, single-arm study, NURTURE (NCT02386553) using Nusinersen in presymptomatic infants [
Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study.
] showed that not only all 25 children were alive and all achieved the ability to sit without support, but also that with few exceptions, most also achieved the ability to walk independently. Interestingly, infants with 3 SMN2 copy number participants were achieving these milestones tracking along the normal development curves.
Preliminary data recently shown at various conferences, using risdiplam (RAINBOWFISH, NCT03779334) or onasemnogene abeparvovec (SPR1NT, NCT03505099) in ongoing open-label pre-symptomatic studies suggest similar efficacy and provide further evidence that initiation of treatment in presymptomatic patients can provide a much larger clinical effect than in symptomatic patients, highlighting the need for neonatal screening.
Neonatal screening probably represents one of the most important challenges over the next few years. The emerging exciting data from clinical trials in presymptomatic patients has reinforced the need to [
] add SMA to the newborn screening panels. After the FDA approval of nusinersen in 2018 approximately 30 states have adopted adding SMA to the US State's panel. Screening programs, often in the form of pilot studies have also started in some European countries. While there is consensus that the screening is much needed at the time new therapies are available and there is evidence of the efficacy in presymptomatic patients, there is less consensus on which patient, once identified, should be treated. A panel of US experts in 2017 recommended treatment of all patients with 2 or 3 copies of SMN2 [
]. These recommendations have not been adopted in all the other countries and the inclusion criteria for treating presymptomatic patients according to SMN2 copy number is still variable ranging from 2 to 4 copies.
Other new challenges include a better understanding of new phenotypes and the need to adapt standards of care. The new therapies have completely changed the progression of the disease course in all SMA types and there is increasing evidence of new phenotypes within each form that were not previously observed. Treated type 1 patients are not only surviving longer but also consistently show an improvement of their functional abilities and often acquire developmental milestones, including unsupported sitting, that had never previously been achieved in type I SMA [
. The unexpected abilities achieved in treated patients are however often associated with signs that need further attention, such as the presence of kyphosis and scoliosis that require careful surveillance and the use of postural devices and orthoses. Similarly, in children with SMA-II who acquire the ability to walk, the gait is often different from that observed in ambulant type III, probably related to the fact that treated type II patients may already have more muscle impairment than in type 3 patients, as also suggested by muscle MRI studies, and may use additional muscles for compensation. There is therefore the need to record all the clinical features observed in the treated patients in order to establish the variability of the new phenotypes and contribute to the evidence of the new course of progression in patients treated with different drugs. Care recommendations, even if revised relatively recently, will also need to be further revised in order to accommodate the new clinical features associated to the emerging phenotypes.
Finally, work is in progress to validate metabolomic and proteomic biomarkers that have been identified as possible prognostic biomarkers in SMA patients [
. Particular attention has been paid to light chain and phosphorylated heavy chain neurofilaments levels in blood and CSF in both pre-symptomatic and symptomatic patients. Other biomarkers include circulating serum miRNA [
Eugenio Mercuri reports personal fees from NOVARTIS/AVEXIS, ROCHE, BIOGEN S.R.L., SCHOLAR ROCK for advisory boards and as PI, outside the submitted work. He is affiliated to an institution that receives funds for a SMA disease registry (ISMAR);
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Zwei fruhinfantilehereditare Falle von progressive r Muskelatrophie unter dem bilde der dystrophie, aber auf neurotisscher grundlage.
Hereditary proximal spinal muscularatrophy: single or multiple genes?.
(In: Barbeau A, eds, B J R editor)2nd international congress on neurogenetics and neuro-opthalmology. Amasterdam Excerpta Medica,
Montreal1969: 17-23 (September 1967)
Hausmanowa-Petrusewicz I. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients.
Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.
Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics.
Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study.
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