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Treating neonatal spinal muscular atrophy: A 21st century success story?
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Treating neonatal spinal muscular atrophy: A 21st century success story? Eduardo F. Tizzano Department of Clinical and Molecular Genetics, Hospital Valle Hebron, Barcelona, Spain Medicine Genetics Group, Valle Hebron Research Institute (VHIR), Barcelona, Spain
ARTICLE INFO
ABSTRACT
Keywords: Spinal muscular atrophy Early diagnosis and intervention Advanced therapies Genetic counselling Antisense oligonucleotides Gene therapy
Severe spinal muscular atrophy is an autosomal recessive motor neuron disorder characterized by rapidly progressive hypotonia and weakness with respiratory complications and fatal outcome. It is caused by absence or pathogenic variants in the SMN1 gene. Knowledge and advances of the genetics of the disease allowed the development of tailored therapies that has changed clinical trajectories with evolving phenotypes. Several clinical investigations demonstrate that early diagnosis and intervention are essential for improved response to treatment and better prognosis. Therapeutic interventions that are effective at pre-symptomatic or early stages of the disease creates the need for awareness, expedite diagnosis and consideration of newborn screening programs.
1. Introduction/overview The field of rare diseases which are mostly of genetic origin have been revolutionized during the last years. Beyond basic research of aetiology and physiopathology, advances include precise clinical and molecular diagnosis (mostly achieved with the arrival of next generation sequencing and genomic analysis), comprehensive and multidisciplinary care/follow up of the patients and finally the opportunity for treatment and development of specific therapies [1]. Indeed, the knowledge generated from the molecular bases of many rare genetic diseases is giving rise to the clinical investigation of very specific advanced therapies, either in the modification or replacement of the affected genes, in the modulation of the RNA or in the metabolism and function of the corresponding proteins. Spinal muscular atrophy (SMA) linked to 5q is an autosomal recessive neuromuscular disorder caused by degeneration of alpha motor neurons of the spinal cord anterior horns. The main manifestation of the disease is muscle weakness by denervation followed by respiratory failure and infant death in the most severe cases. SMA is one of the commonest severe hereditary disorders of infancy and early childhood, with an incidence estimated of 1/6000 to 1/10,000 births and a carrier frequency of 1/35 to 1/50 [2]. SMA constitutes a truly example on how all these progresses contributed to generate tailored advanced therapies that are successfully applied to patients (Fig. 1). Originally described by Guido Werdnig and Johann Hoffmann at the end of the XIX century [3], in 1995 the SMN1 gene was identified as the cause of the disease [4]. The knowledge of the genetic and genotype-phenotype correlations together with the generation of animal models contributed to develop preclinical studies where to test therapeutic alternatives and quickly start clinical trials (CT) in humans
by the beginning of this decade. Indeed, two advanced therapies in SMA have been already approved by FDA. An antisense oligonucleotide that affects splicing of the premRNA (nusinersen-Spinraza®) in December 2016 [5] and a self-complementary adeno associated virus serotype 9 (AAV9) gene therapy (Onasemnogene Abeparvovec, ZolgenSMA®) recently in May this year 2019 [6]. One of the main conclusions of the CTs is that the early the treatment with these medications, the better the response. This review intends to stimulate neonatologists for awareness, prompt and timely diagnosis and consider opportunities to early intervention in these patients, in particular envisaged by programs of newborn screening (NBS). 2. Clinical classifications and genetic bases Historically, SMA patients have been designated mainly by eponymous names of research neurologists that made description of the different manifestations of the disease. Thus, Werdnig-Hoffmann, Dubowitz and Wohlfahrt Kugelberg Welander SMA forms were traditionally employed [3]. SMA clinical manifestations range from serious congenital forms to minimal manifestations in adulthood and a consensus statement to classify SMA in three main types based on age at onset and maximum milestones achieved have been reported in 1992 [7] (Fig. 1). Type I, the most severe form, manifests early in the first weeks or months of life with generalized hypotonia. More than 90% of these cases will have died at 2 years of age due to respiratory problems that involve tracheostomy and invasive mechanical ventilation [8,9]. In the type II form, patients already acquire the ability to sit down but are permanently confined to a wheelchair, with respiratory complications, scoliosis and contractures. In the type III form, patients can walk, but
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Please cite this article as: Eduardo F. Tizzano, Early Human Development, https://doi.org/10.1016/j.earlhumdev.2019.104851
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Fig. 1. Chronology and milestones of SMA from the early description in the XIX century to the actual approved therapies. Dashed line square represents the ongoing issues that are considered in view of the new therapeutic scenario. Note the increasing interest in SMA during the last years involving more researchers with >400 publications in 2018 and increasing yearly. Table 1 Spinal muscular atrophy classification considering a continuous spectrum of manifestations, natural history of the disease and SMN2 copy number (based on references 7,10,15,35,37). The therapeutic scenario and evolving phenotypes as well as early diagnosis and intervention may probably be adapted to change this classification in the near future considering time of disease evolution and age of initiation of therapy together with SMN2 information and other biomarkers. Eponymus
Main SMA type
Werdnig Hoffmann disease
1
Dubowitz intermediate form Wohlfahrt-Kugelberg-Welander disease
Adult form
Subtype
Onset
Milestones achieved
Prevalent SMN2 copies
Prenatal
None
1
1 1 2 2 3
1A (some authors type 0) 1B 1C 2A 2B 3A
<3 M >3 M >6 M Usually after 12 months Between 18- to 36 months
2 3 3 3 3
3
3B
>3 years
4
4
Second/third decade of life
Poor or none cephalic control Cephalic control Weak sitter Strong sitter Walker Loss of deambulation childhood Walker Loss of ambulation adolescenceadult Walker
generally lose that ability in later years (see Table 1 for details and subclassification of SMA types) [10]. All these SMA types are the result of lower amounts of SMN protein which is encoded by two genes: Survival motor neuron 1 (SMN1) and Survival motor neuron 2 (SMN2) both located in a complex region of chromosome 5 (5q13) [4]. Although the SMN protein is ubiquitously expressed in all cells to guarantee living and survival, lower levels, as seen in SMA, are insufficient to protect motor neurons and the neuromuscular system [11,12]. Pathogenic variants in the SMN1 gene cause SMA disease such as homozygous deletion (90%), gene conversion events (5%) or subtle pathogenic variants (3–4%) [13]. SMN2 is a paralogous gene of SMN1 differing only by few nucleotides. Both SMN genes encode for identical proteins although most of SMN1 transcripts are full length (FL-SMN) whereas the majority of SMN2 transcripts lack exon 7 due to alternative splicing (Δ7-SMN). A single translational silent C to T transition within exon 7 transforms an exonic splicing enhancer in an exonic splicing
3–4 4
silencer, affecting the splicing of this exon in primary SMN transcripts [14]. Thus, SMN2 encodes mainly a protein (SMNΔ7) which does not oligomerize efficiently and is unstable. SMN2 is, however, able to produce some complete transcripts and protein although is insufficient to avoid the disease. Given the absence of SMN1, the number of SMN2 copies act as a phenotypic modifier of the disease. The more the copies, the less severe is the phenotype. In practice, around 90% of type I patients have two copies of SMN2 and around 85% of type II have three SMN2 copies. Type III patients may present with three or four copies [15]. Therefore, the correlation is not absolute and prognosis based on SMN2 copy number is not consistent, but prediction may be applicable for a subset of patients. The main prognostic factors are the age of onset of manifestations and the degree of respiratory compromise given that phenotypic discordances should be considered in different situations regarding SMN2 copies. For example three SMN2 copies have been reported in patients with type IC, type II and type III (Table 1). Another 2
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complex situation is the detection in a given family of asymptomatic haploidentical siblings with absence of the SMN1 gene and the same SMN2 copy number [16]. This situation has been observed in families with type II, III and IV SMA. 3. Developmental and neonatal aspects of SMA Studies in foetuses predicted to develop severe SMA disease indicate that some aspects of SMA pathology begin prenatally when neuromuscular development occurs [17]. Data in animal models as in humans indicate that higher levels of SMN are required prenatally in comparison with the postnatal period [18–20]. These high levels of SMN may be necessary for normal development and decay and developmental reduction of SMN, as occur in SMA, may increase sensitivity and prompt MNs to specific defects. The maintenance of the required levels of SMN protein is essential to guarantee development and survival given that none individual has been described with absence of both, SMN1 and SMN2 genes, indicating that SMN protein is crucial for survival. Furthermore, the main pathology in SMA affects the neuromuscular system, but there are several clinical reports and animal studies that other tissues and organs are involved particularly in the most severe forms of the disease which may be consequences of substantial reduction of SMN protein. These may include autonomic nervous system involvement, congenital heart defects, vascular defects, liver, pancreas, intestine and metabolic deficiencies [21,22]. Around 3 out of 4 type 0 SMA cases and one SMN2 copy have cardiac malformation and most of these patients die in the first weeks of life. Interestingly, it has recently been reported that diffuse and progressive brain abnormalities occurs also in patients with SMA type 0 and one SMN2 copy who survived longer than 1 year [23]. Severe cardiac and brain involvement may likely be manifestations of extreme SMA phenotypes when there is significant decrease of SMN protein beyond the neuromuscular system. Further investigations to identify pathological changes in all tissues potentially affected by SMA are essential for successfully developing and application of new therapeutic approaches. A neonate with SMA may be asymptomatic, but neonatologists should look for early signs and manifestations of the disease (Table 2). In general areflexia precedes hypotonia and muscle weakness albeit in some cases manifestations are observed altogether, particularly when a delay of initial suspicion postpones the indication of SMN1 test that will confirm the disease in the vast majority of the cases [13]. In rare situations, as illustrated in Fig. 2, neonatal manifestations of vascular dysautonomia precedes the observation of weakness or areflexia and should be taken into account in differential diagnosis (Fig. 2). 4. The therapeutic scenario
Fig. 2. A neonate presented at first weeks of life with persistent purple and cold feet together with cutis marmorata representing dysautonomic manifestations. Although this finding may transiently appears in normal newborns, when there are marked appearance and persistence it is prudent to look for other SMA manifestations. In this patient areflexia, weakness and hypotonia appeared around three months of life. SMA diagnosis was confirmed by genetic testing (patient data and picture with permission obtained by the parents).
Preclinical successful therapies in murine models of SMA have been observed with different approaches that opened the gate to initiate CTs Table 2 SMA manifestations that may appear in neonates.
• Areflexia - Hypotonia • Weakness fasciculations • Tongue shaped thorax • Bell paradoxical breath • Diaphragmatic and/or hypercapnia • Hypoxemia cry • Weak or feeding problems • Swallowing manifestations: increase of sweating, bradycardia, distal necrosis, • Dysautonomic impaired regulation of vascular tone, irregular skin responses to temperature
in patients [24–26]. The first to be initiated in humans was the nusinersen clinical program that started in 2011. Nusinersen (Spinraza®) is an 18-mer antisense oligonucleotide that can modify SMN2 splicing to include exon 7 producing increased amounts of full-length SMN protein [10]. Efficacy has been demonstrated in phase 3 studies with intrathecal injection and using a sham procedure as placebo in type I SMA infants <6 months (ENDEAR, n = 121) and late onset non-ambulant SMA patients (between 2 and 12 years) (CHERISH, n = 126). These results led to the approval of the first tailored treatment for SMA in 2016 by FDA and in 2017 by EMA [5,27] (Fig. 1). Open label studies as well as real world data confirmed the safety and efficacy in a broader cohort of SMA patients (>8000 worldwide) [28] (Table 3). Type I
changes
defects: mainly septal defects and abnormalities of the cardiac outflow tract • Cardiac problems: hypoglycemia, hypercalcemia • Metabolic contractures • Joint • Osteopenia/bone fractures
3
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Table 3 Characteristic of advanced therapeutic specific SMN dependent approaches under clinical investigation in SMA. Nusinersen (Spinraza®)
AVXS-101 (ZolgenSMA®)
RG7916 (Risdiplam®)
Type of therapy
Antisense oligonucleotide specific to ISSN1 in intron 7 ASO–ISSN1
Pyridazine derivative that increase binding of exon 7 with U1snRNP
Intracellular place of action Mechanism of action
Pre-mRNA in nuclei to include exon 7 Increase amount of complete SMN protein from SMN2
Administration route Dose and frequency of administration Target Type of SMA patients treated
Intrathecally (IT) Four loading doses (12 mg each) and maintenance every 4 months Motor neurons and other CNS cells Type I and II and presymptomatic (Nurture) ongoing
Self-complementary adeno associated virus with human coding SMN1 scAAV9.CB.SMN1 Incorporates in nuclei as episomes Production of SMN protein from SMN1 Intravenously One dose of 2.014 vg/kg
Number of patients treated
Clinical trials 285 Expanded access program 843 Prescription >8000 The majority of AEs and SAEs consistent with the nature and frequency of events typically occurring in the context of SMA or lumbar puncture procedure FDA all SMA types (Dec 2016) EMA (June 2017)
Safety Approval
All non-dividing cells of the organism Type I (type II IT) and presymptomatic (Sprint) ongoing Around 150 (type I-type II) Elevations in ALT/AST in some patients, treatable with prednisolone Unknown long-term safety profile FDA (type I - May 2019) Expanded CTs ongoing
Pre-mRNA in nuclei to include exon 7 Increase amount of complete SMN protein from SMN2 Oral 5 mg/day or 0.25 mg/kg All cells of the organism Type I-type II-type III and presymptomatic (Rainbowfish) ongoing Around 200 (type I, II, III) Favorable safety profile to date Monitoring eye changes based on preclinical data with similar compound CTs ongoing
for SMA which, in fact, may be not opposite but potentially complementary(Table 3). Other medications, SMN independent, are under investigation in SMA such as neuroprotectors, neuromuscular junction stabilizers and muscle function activators (www.clinicaltrials.gov) and it is possible that once the efficacy of all of these compounds is proven, combinatorial approaches with SMN tailored therapies may be investigated and protocolized [29].
patients live longer with motor milestones never observed previously in these patients. However, some complications may appear such as scoliosis, hip dislocation or foot deformities as part of the evolving phenotypes [29]. Motor improvement in some patients may not be clearly observed because are no responders or become responders later [5]. Patients involved in both, ENDEAR and CHERISH CTs are currently followed up in another trial (SHINE, NCT02594124). An open-label CT in pre-symptomatic patients with two (n = 15) and three (n = 10) SMN2 copies starting treatment before 6 weeks of age is also currently ongoing (NURTURE, NCT02386553). The interim analysis in May 2019 indicated that all children were alive, without permanent ventilation and had reached the sitting position. The majority of patients of this CT after at least two years of treatment are able to stand alone and walk independently [30,31]. Personal individual cases treated pre-symptomatically have been presented or reported in several meetings and also confirm the treatment success [28]. The second program started in 2014 and consisted in the single intravenous injection of systemic-delivered AAV9 with the coding part of SMN1 as gene therapy (AVXS-101) to replace defective SMN1 in 15 infants with SMA type I [6,32]. All patients are alive without requiring permanent mechanical ventilation and improving motor milestones [33]. AVXS-101 (Onasemnogene Abeparvovec-xioi, ZolgenSMA®) has been recently approved in May 2019 by FDA for patients <2 years with type I SMA and is currently under review by the EMA. At present this gene therapy treatment is considered the most expensive medication in the world [34]. Studies are ongoing with ZolgenSMA treating diverse population of patients and include a larger population of type I SMA patients (STR1VE, NCT03306277; STR1VE EU, NCT03461289) as well as type II for a single intrathecal injection (STRONG, NCT03381729) and pre-symptomatic cases under of 6 weeks for single intravenous dose (SPR1NT, NCT03505099). As in the case of nusinersen/Spinraza® there is substantial evidence that when gene therapy is initiated early, there is better motor response and respiratory outcomes [32,33]. Other experimental therapies, including for example oral medications that also increase the inclusion of exon 7 are under clinical investigation. The oral compound RG7916 or Risdiplam® is a splicing modifier which is currently in phase 3 in SMA type I patients (FIREFISH, NCT02913482), type II-III patients (SUNFISH, NCT02908685) and pre-symptomatic babies (RAINBOWFISH, NCT03779334) (www. clinicaltrials.gov). Table 3 summarizes the mechanism of action, application and main characteristics of these three main advanced SMN dependent therapies
5. Conclusions: towards expedite diagnosis and early intervention Several conclusions can be formulated in view of published investigations available and sustained data that is permanently increasing and updated in the ongoing clinical trials and real world evidence. First, there is a changing/evolving phenotype in all patients treated and some patients may not be responders, are slow responders or becoming responders after several months of treatment [29]. Second, although medication has demonstrated efficacy, patients with severe SMA are fragile, very compromised and may also die as happened with some patients in the ENDEAR trial. For best results of therapy, patients need a closer follow up with the consensus standards of care in the context of a multidisciplinary team [35,36]. Third, the disease duration prior to treatment as well as the age of initiation of treatment of the patients appear to be strong predictors of efficacy [5,28,33]. There is a rapid progression of SMA1 and a delay in treatment would likely impact the evolution with a greater irreversible loss of function and reduced motor response. Thus, it is important to promote awareness for early detection of the disease and expedite diagnosis. Given the encouraging results of different therapies investigated, and because there is evidence that early intervention and treatment is associated with better prognosis and evolution there is now strong consensus that newborn screening (NBS) should be implemented as secondary prevention of SMA [37]. Facing this new scenario of gradual implementation of SMA NBS, it is envisaged that most of the neonates with SMA will be genetically diagnosed at a presymptomatic stage [37]. This would allow recollection and registry of baseline data and search for clinical manifestations of each patient (as compiled in Table 2) together with information on functional scales such as Children´s Hospital of Philadelpia Infant Test of Neuromuscular Disorders (CHOP INTEND) and on electromyography such as compound muscle action potential (CMAP) or motor unit number estimation (MUNE). The number of SMN2 copies could be used as an initial predictor of SMA type albeit it is of no proven value as a surrogate marker of ongoing disease activity or response to treatment [15]. In this matter, other promising 4
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biomarkers such as phosphorylated neurofilament heavy chain (pNFeH) levels in plasma of SMA patients are under investigation [38]. Communication of diagnosis as well as adequate genetic counselling have to evolve considering that the trajectory of the disease is now changing due to the success of novel therapies to improve motor function in these patients [37]. Shared decision making for treatment and psychological support of the families are critical to cope with the impact of the disease. High cost of these treatments and different health insurances according to countries raises also concerns about access and equity that should be considered. The concept of SMA as an untreatable disease has now fundamentally changed with potential life-transforming therapies, creating new expectations and challenges for patients, families and health care providers.
[16]
[17] [18]
[19]
[20]
Acknowledgments
[21]
The author is indebted to all SMA families and working colleagues and is recipient of Daniel Bravo Foundation and supported by the Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and cofunded with ERDF funds (Grant No. FIS PI18/000687) for SMA research grants.
[22] [23]
[24]
Declaration of competing interest
[25]
The author has received grant support to conduct clinical trials on SMA from Ionis/Biogen and serves as a consultant to Biogen, AveXis, Roche, Biologix, and Cytokinetics.
[26]
References
[27]
[1] Tizzano EF. Advanced therapies in rare diseases: the example of spinal muscular atrophy. Med Clin (Barc). 2018 Oct 12;151(7):275–277. doi:https://doi.org/10.1016/j. medcli.2018.03.001. Epub 2018 Apr 21. English, Spanish. PubMed PMID: 29685310. [2] E.A. Sugarman, N. Nagan, H. Zhu, V.R. Akmaev, Z. Zhou, E.M. Rohlfs, K. Flynn, B.C. Hendrickson, T. Scholl, D.A. Sirko-Osadsa, et al., Pan-ethic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of > 72,400 specimens, Eur. J. Hum. Genet. 20 (2012) 27–32. [3] V. Dubowitz, Ramblings in the history of spinal muscular atrophy, Neuromuscul. Disord. 19 (1) (2009 Jan) 69–73. [4] S. Lefebvre, L. Bürglen, S. Reboullet, O. Clermont, P. Burlet, L. Viollet, B. Benichou, C. Cruaud, P. Millasseau, M. Zeviani, et al., Identification and characterization of a spinal muscular atrophy-determining gene, Cell 80 (1995) 155–165. [5] R.S. Finkel, E. Mercuri, B.T. Darras, A.M. Connolly, N.L. Kuntz, J. Kirschner, et al., ENDEAR study group. Nusinersen versus sham control in infantile-onset spinal muscular atrophy, N. Engl. J. Med. 377 (2017) 1723–1732. [6] J.R. Mendell, S. Al-Zaidy, R. Shell, W.D. Arnold, L.R. Rodino-Klapac, T.W. Prior, et al., Single-dose gene-replacement therapy for spinal muscular atrophy, N. Engl. J. Med. 377 (2017) 1713–1722. [7] T. Munsat, K. Davies, International SMA consortium meeting (26-28 June 1992, Bonn, Germany), Neuromuscul. Disord. 2 (1992) 423–428. [8] R.S. Finkel, M.P. McDermott, P. Kaufmann, B.T. Darras, W.K. Chung, D.M. Sproule, et al., Observational study of spinal muscular atrophy type I and implications for clinical trials, Neurology 83 (2014) 810–817. [9] S.J. Kolb, C.S. Coffey, J.W. Yankey, K. Krosschell, W.D. Arnold, S.B. Rutkove, K.J. Swoboda, S.P. Reyna, A. Sakonju, B.T. Darras, R. Shell, et al., Natural history of infantile-onset spinal muscular atrophy, Ann. Neurol. 82 (6) (2017 Dec) 883–891. [10] K. Talbot, E.F. Tizzano, The clinical landscape for SMA in a new therapeutic era, Gene Ther. 24 (2017) 529–533. [11] S. Lefebvre, P. Burlet, Q. Liu, S. Bertrandy, O. Clermont, A. Munnich, G. Dreyfuss, J. Melki, Correlation between severity and SMN protein level in spinal muscular atrophy, Nat. Genet. 16 (3) (1997 Jul) 265–269. [12] C. Soler-Botija, I. Cuscó, L. Caselles, E. López, M. Baiget, E.F. Tizzano, Implication of fetal SMN2 expression in type I SMA pathogenesis: protection or pathological gain of function? J. Neuropathol. Exp. Neurol. 64 (2005) 215–223. [13] L. Alías, S. Bernal, P. Fuentes-Prior, M.J. Barceló, E. Also, R. Martínez-Hernández, F.J. Rodríguez-Alvarez, Y. Martín, E. Aller, E. Grau, A. Peciña, et al., Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene, Hum. Genet. 125 (2009) 29–39. [14] C.L. Lorson, E. Hahnen, E.J. Androphy, B. Wirth, A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy, Proc. Natl. Acad. Sci. U. S. A. 96 (11) (1999 May 25) 6307–6311. [15] M. Calucho, S. Bernal, L. Alias, F. March, A. Venceslá, F.J. Rodríguez-Álvarez, E. Aller, R. Fernández, S. Borrego, J.M. Millán, et al., Correlation between SMA type
[28] [29] [30]
[31]
[32]
[33]
[34] [35]
[36]
[37]
[38]
5
and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2,834 reported cases, Neuromuscul. Disord. 28 (2018) 208–215. S. Bernal, E. Also-Rallo, R. Martínez-Hernández, L. Alías, F.J. Rodríguez-Alvarez, J.M. Millán, C. Hernández-Chico, M. Baiget, E.F. Tizzano, Plastin 3 expression in discordant spinal muscular atrophy (SMA) siblings, Neuromuscul. Disord. 21 (6) (2011 Jun) 413–419. E.F. Tizzano, D. Zafeiriou, Prenatal aspects in spinal muscular atrophy: from early detection to early presymptomatic intervention, Eur. J. Paediatr. Neurol. 22 (6) (2018 Nov) 944–950. P. Burlet, C. Huber, S. Bertrandy, M.A. Ludosky, I. Zwaenepoel, O. Clermont, J. Roume, A.L. Delezoide, J. Cartaud, A. Munnich, S. Lefebvre, The distribution of SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy, Hum. Mol. Genet. 7 (12) (1998 Nov) 1927–1933. M.G. Boza-Morán, R. Martínez-Hernández, S. Bernal, K. Wanisch, E. Also-Rallo, A. LeHeron, L. Alías, C. Denis, M. Girard, J.K. Yee, E.F. Tizzano, R.J. Yáñez-Muñoz, Decay in survival motor neuron and plastin 3 levels during differentiation of iPSCderived human motor neurons, Sci. Rep. 5 (2015) 11696. C.J. Sumner, Crawford TO, Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain, J. Clin. Invest. 128 (8) (2018 Aug 1) 3219–3227. G. Hamilton, T. Gillingwater, Spinal muscular atrophy: going beyond the motor neuron, Trends Mol. Med. 19 (2013) 40–50. M. Shababi, C.L. Lorson, S.S. Rudnik-Schöneborn, Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J. Anat. 224 (1) (2014 Jan) 15–28. Mendonça RH, Rocha AJ, Lozano-Arango A, Diaz AB, Castiglioni C, Silva AMS, Reed UC, Kulikowski L, Paramonov I, Cuscó I, Tizzano EF, Zanoteli E. Severe brain involvement in 5q spinal muscular atrophy type 0. Ann Neurol. 2019 Jul 13. doi: https://doi.org/10. 1002/ana.25549. [Epub ahead of print] PubMed PMID: 31301241. K.D. Foust, X. Wang, V.L. Mcgovern, L. Braun, K. Adam, A.M. Haidet, et al., Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN, Nat. Biotechnol. 28 (2010) 271–274. Y. Hua, K. Sahashi, F. Rigo, G. Hung, G. Horev, C.F. Bennett, A.R. Krainer, Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model, Nature 478 (7367) (2011 Oct 5) 123–126. N.A. Naryshkin, M. Weetall, A. Dakka, J. Narasimhan, X. Zhao, Z. Feng, K.K. Ling, G.M. Karp, H. Qi, M.G. Woll, et al., Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy, Science 345 (6197) (2014 Aug 8) 688–693. E. Mercuri, B.T. Darras, C.A. Chiriboga, J.W. Day, C. Campbell, A.M. Connolly, et al., CHERISH study group. Nusinersen versus sham control in later-onset spinal muscular atrophy, N. Engl. J. Med. 378 (2018) 625–635. T. Gidaro, L. Servais, Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps, Dev. Med. Child Neurol. 61 (1) (2019 Jan) 19–24. E.F. Tizzano, R.S. Finkel, Spinal muscular atrophy: a changing phenotype beyond the clinical trials, Neuromuscul. Disord. 27 (2017 Oct) 883–889. E. Bertini, W.-L. Hwu, S.P. Reyna, W. Farwell, S. Gheuens, P. Sun, Z.J. Zhong, D. De Vivo, et al., Efficacy and safety of nusinersen in infants with presymptomatic spinal muscular atrophy (SMA): interim results from the NURTURE study, Eur. J. Paediatr. Neurol. 21 (2017 Jun 1) e14. De Vivo, D.; Bertini, E.; Swoboda, K.J.; et al., Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study Neuromusc DIsord (in press) DOI: https:// doi.org/10.1016/j.nmd.2019.09.007. S. Al-Zaidy, A.S. Pickard, K. Kotha, L.N. Alfano, L. Lowes, G. Paul, K. Church, K. Lehman, D.M. Sproule, O. Dabbous, B. Maru, K. Berry, W.D. Arnold, J.T. Kissel, J.R. Mendell, R. Shell, Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy, Pediatr. Pulmonol. 54 (2) (2019 Feb) 179–185. Lowes LP, Alfano LN, Arnold WD, Shell R, Prior TW, McColly M, Lehman KJ, Church K, Sproule DM, Nagendran S, Menier M, Feltner DE, Wells C, Kissel JT, AlZaidy S, Mendell J. Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose Gene replacement therapy. Pediatr Neurol. 2019 May 13. pii: S0887 8994(19)30280–2. https://www.npr.org/sections/health-shots/2019/05/24/725404168/at-2-125million-new-gene-therapy-is-the-most-expensive-drug-ever?t=1565638635392. E. Mercuri, R.S. Finkel, F. Muntoni, B. Wirth, J. Montes, M. Main, E.S. Mazzone, M. Vitale, B. Snyder, S. Quijano-Roy, et al., Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care, Neuromuscul. Disord. 28 (2) (2018 Feb) 103–115. R.S. Finkel, E. Mercuri, O.H. Meyer, A.K. Simonds, M.K. Schroth, R.J. Graham, J. Kirschner, S.T. Iannaccone, T.O. Crawford, S. Woods, F. Muntoni, B. Wirth, J. Montes, M. Main, E.S. Mazzone, M. Vitale, B. Snyder, S. Quijano-Roy, E. Bertini, R.H. Davis, Y. Qian, T. Sejersen, SMA Care group, Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics, Neuromuscul. Disord. 28 (3) (2018 Mar) 197–207. Serra-Juhe C, Tizzano EF. Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors. Eur. J. Hum. Genet. 2019 May 3. doi:https://doi.org/10.1038/s41431-0190415-4. [Epub ahead of print] Review. PubMed PMID: 31053787. B.T. Darras, T.O. Crawford, R.S. Finkel, E. Mercuri, D.C. De Vivo, M. Oskoui, E.F. Tizzano, M.M. Ryan, F. Muntoni, G. Zhao, J. Staropoli, A. McCampbell, M. Petrillo, C. Stebbins, S. Fradette, W. Farwell, C.J. Sumner, Neurofilament as a potential biomarker for spinal muscular atrophy, Ann. Clin. Transl. Neurol. 6 (5) (2019 Apr 17) 932–944.
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Treating neonatal spinal muscular atrophy: A 21st century success story? Eduardo F. Tizzano Department of Clinical and Molecular Genetics, Hospital Valle Hebron, Barcelona, Spain Medicine Genetics Group, Valle Hebron Research Institute (VHIR), Barcelona, Spain
ARTICLE INFO
ABSTRACT
Keywords: Spinal muscular atrophy Early diagnosis and intervention Advanced therapies Genetic counselling Antisense oligonucleotides Gene therapy
Severe spinal muscular atrophy is an autosomal recessive motor neuron disorder characterized by rapidly progressive hypotonia and weakness with respiratory complications and fatal outcome. It is caused by absence or pathogenic variants in the SMN1 gene. Knowledge and advances of the genetics of the disease allowed the development of tailored therapies that has changed clinical trajectories with evolving phenotypes. Several clinical investigations demonstrate that early diagnosis and intervention are essential for improved response to treatment and better prognosis. Therapeutic interventions that are effective at pre-symptomatic or early stages of the disease creates the need for awareness, expedite diagnosis and consideration of newborn screening programs.
1. Introduction/overview The field of rare diseases which are mostly of genetic origin have been revolutionized during the last years. Beyond basic research of aetiology and physiopathology, advances include precise clinical and molecular diagnosis (mostly achieved with the arrival of next generation sequencing and genomic analysis), comprehensive and multidisciplinary care/follow up of the patients and finally the opportunity for treatment and development of specific therapies [1]. Indeed, the knowledge generated from the molecular bases of many rare genetic diseases is giving rise to the clinical investigation of very specific advanced therapies, either in the modification or replacement of the affected genes, in the modulation of the RNA or in the metabolism and function of the corresponding proteins. Spinal muscular atrophy (SMA) linked to 5q is an autosomal recessive neuromuscular disorder caused by degeneration of alpha motor neurons of the spinal cord anterior horns. The main manifestation of the disease is muscle weakness by denervation followed by respiratory failure and infant death in the most severe cases. SMA is one of the commonest severe hereditary disorders of infancy and early childhood, with an incidence estimated of 1/6000 to 1/10,000 births and a carrier frequency of 1/35 to 1/50 [2]. SMA constitutes a truly example on how all these progresses contributed to generate tailored advanced therapies that are successfully applied to patients (Fig. 1). Originally described by Guido Werdnig and Johann Hoffmann at the end of the XIX century [3], in 1995 the SMN1 gene was identified as the cause of the disease [4]. The knowledge of the genetic and genotype-phenotype correlations together with the generation of animal models contributed to develop preclinical studies where to test therapeutic alternatives and quickly start clinical trials (CT) in humans
by the beginning of this decade. Indeed, two advanced therapies in SMA have been already approved by FDA. An antisense oligonucleotide that affects splicing of the premRNA (nusinersen-Spinraza®) in December 2016 [5] and a self-complementary adeno associated virus serotype 9 (AAV9) gene therapy (Onasemnogene Abeparvovec, ZolgenSMA®) recently in May this year 2019 [6]. One of the main conclusions of the CTs is that the early the treatment with these medications, the better the response. This review intends to stimulate neonatologists for awareness, prompt and timely diagnosis and consider opportunities to early intervention in these patients, in particular envisaged by programs of newborn screening (NBS). 2. Clinical classifications and genetic bases Historically, SMA patients have been designated mainly by eponymous names of research neurologists that made description of the different manifestations of the disease. Thus, Werdnig-Hoffmann, Dubowitz and Wohlfahrt Kugelberg Welander SMA forms were traditionally employed [3]. SMA clinical manifestations range from serious congenital forms to minimal manifestations in adulthood and a consensus statement to classify SMA in three main types based on age at onset and maximum milestones achieved have been reported in 1992 [7] (Fig. 1). Type I, the most severe form, manifests early in the first weeks or months of life with generalized hypotonia. More than 90% of these cases will have died at 2 years of age due to respiratory problems that involve tracheostomy and invasive mechanical ventilation [8,9]. In the type II form, patients already acquire the ability to sit down but are permanently confined to a wheelchair, with respiratory complications, scoliosis and contractures. In the type III form, patients can walk, but
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Please cite this article as: Eduardo F. Tizzano, Early Human Development, https://doi.org/10.1016/j.earlhumdev.2019.104851
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Fig. 1. Chronology and milestones of SMA from the early description in the XIX century to the actual approved therapies. Dashed line square represents the ongoing issues that are considered in view of the new therapeutic scenario. Note the increasing interest in SMA during the last years involving more researchers with >400 publications in 2018 and increasing yearly. Table 1 Spinal muscular atrophy classification considering a continuous spectrum of manifestations, natural history of the disease and SMN2 copy number (based on references 7,10,15,35,37). The therapeutic scenario and evolving phenotypes as well as early diagnosis and intervention may probably be adapted to change this classification in the near future considering time of disease evolution and age of initiation of therapy together with SMN2 information and other biomarkers. Eponymus
Main SMA type
Werdnig Hoffmann disease
1
Dubowitz intermediate form Wohlfahrt-Kugelberg-Welander disease
Adult form
Subtype
Onset
Milestones achieved
Prevalent SMN2 copies
Prenatal
None
1
1 1 2 2 3
1A (some authors type 0) 1B 1C 2A 2B 3A
<3 M >3 M >6 M Usually after 12 months Between 18- to 36 months
2 3 3 3 3
3
3B
>3 years
4
4
Second/third decade of life
Poor or none cephalic control Cephalic control Weak sitter Strong sitter Walker Loss of deambulation childhood Walker Loss of ambulation adolescenceadult Walker
generally lose that ability in later years (see Table 1 for details and subclassification of SMA types) [10]. All these SMA types are the result of lower amounts of SMN protein which is encoded by two genes: Survival motor neuron 1 (SMN1) and Survival motor neuron 2 (SMN2) both located in a complex region of chromosome 5 (5q13) [4]. Although the SMN protein is ubiquitously expressed in all cells to guarantee living and survival, lower levels, as seen in SMA, are insufficient to protect motor neurons and the neuromuscular system [11,12]. Pathogenic variants in the SMN1 gene cause SMA disease such as homozygous deletion (90%), gene conversion events (5%) or subtle pathogenic variants (3–4%) [13]. SMN2 is a paralogous gene of SMN1 differing only by few nucleotides. Both SMN genes encode for identical proteins although most of SMN1 transcripts are full length (FL-SMN) whereas the majority of SMN2 transcripts lack exon 7 due to alternative splicing (Δ7-SMN). A single translational silent C to T transition within exon 7 transforms an exonic splicing enhancer in an exonic splicing
3–4 4
silencer, affecting the splicing of this exon in primary SMN transcripts [14]. Thus, SMN2 encodes mainly a protein (SMNΔ7) which does not oligomerize efficiently and is unstable. SMN2 is, however, able to produce some complete transcripts and protein although is insufficient to avoid the disease. Given the absence of SMN1, the number of SMN2 copies act as a phenotypic modifier of the disease. The more the copies, the less severe is the phenotype. In practice, around 90% of type I patients have two copies of SMN2 and around 85% of type II have three SMN2 copies. Type III patients may present with three or four copies [15]. Therefore, the correlation is not absolute and prognosis based on SMN2 copy number is not consistent, but prediction may be applicable for a subset of patients. The main prognostic factors are the age of onset of manifestations and the degree of respiratory compromise given that phenotypic discordances should be considered in different situations regarding SMN2 copies. For example three SMN2 copies have been reported in patients with type IC, type II and type III (Table 1). Another 2
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complex situation is the detection in a given family of asymptomatic haploidentical siblings with absence of the SMN1 gene and the same SMN2 copy number [16]. This situation has been observed in families with type II, III and IV SMA. 3. Developmental and neonatal aspects of SMA Studies in foetuses predicted to develop severe SMA disease indicate that some aspects of SMA pathology begin prenatally when neuromuscular development occurs [17]. Data in animal models as in humans indicate that higher levels of SMN are required prenatally in comparison with the postnatal period [18–20]. These high levels of SMN may be necessary for normal development and decay and developmental reduction of SMN, as occur in SMA, may increase sensitivity and prompt MNs to specific defects. The maintenance of the required levels of SMN protein is essential to guarantee development and survival given that none individual has been described with absence of both, SMN1 and SMN2 genes, indicating that SMN protein is crucial for survival. Furthermore, the main pathology in SMA affects the neuromuscular system, but there are several clinical reports and animal studies that other tissues and organs are involved particularly in the most severe forms of the disease which may be consequences of substantial reduction of SMN protein. These may include autonomic nervous system involvement, congenital heart defects, vascular defects, liver, pancreas, intestine and metabolic deficiencies [21,22]. Around 3 out of 4 type 0 SMA cases and one SMN2 copy have cardiac malformation and most of these patients die in the first weeks of life. Interestingly, it has recently been reported that diffuse and progressive brain abnormalities occurs also in patients with SMA type 0 and one SMN2 copy who survived longer than 1 year [23]. Severe cardiac and brain involvement may likely be manifestations of extreme SMA phenotypes when there is significant decrease of SMN protein beyond the neuromuscular system. Further investigations to identify pathological changes in all tissues potentially affected by SMA are essential for successfully developing and application of new therapeutic approaches. A neonate with SMA may be asymptomatic, but neonatologists should look for early signs and manifestations of the disease (Table 2). In general areflexia precedes hypotonia and muscle weakness albeit in some cases manifestations are observed altogether, particularly when a delay of initial suspicion postpones the indication of SMN1 test that will confirm the disease in the vast majority of the cases [13]. In rare situations, as illustrated in Fig. 2, neonatal manifestations of vascular dysautonomia precedes the observation of weakness or areflexia and should be taken into account in differential diagnosis (Fig. 2). 4. The therapeutic scenario
Fig. 2. A neonate presented at first weeks of life with persistent purple and cold feet together with cutis marmorata representing dysautonomic manifestations. Although this finding may transiently appears in normal newborns, when there are marked appearance and persistence it is prudent to look for other SMA manifestations. In this patient areflexia, weakness and hypotonia appeared around three months of life. SMA diagnosis was confirmed by genetic testing (patient data and picture with permission obtained by the parents).
Preclinical successful therapies in murine models of SMA have been observed with different approaches that opened the gate to initiate CTs Table 2 SMA manifestations that may appear in neonates.
• Areflexia - Hypotonia • Weakness fasciculations • Tongue shaped thorax • Bell paradoxical breath • Diaphragmatic and/or hypercapnia • Hypoxemia cry • Weak or feeding problems • Swallowing manifestations: increase of sweating, bradycardia, distal necrosis, • Dysautonomic impaired regulation of vascular tone, irregular skin responses to temperature
in patients [24–26]. The first to be initiated in humans was the nusinersen clinical program that started in 2011. Nusinersen (Spinraza®) is an 18-mer antisense oligonucleotide that can modify SMN2 splicing to include exon 7 producing increased amounts of full-length SMN protein [10]. Efficacy has been demonstrated in phase 3 studies with intrathecal injection and using a sham procedure as placebo in type I SMA infants <6 months (ENDEAR, n = 121) and late onset non-ambulant SMA patients (between 2 and 12 years) (CHERISH, n = 126). These results led to the approval of the first tailored treatment for SMA in 2016 by FDA and in 2017 by EMA [5,27] (Fig. 1). Open label studies as well as real world data confirmed the safety and efficacy in a broader cohort of SMA patients (>8000 worldwide) [28] (Table 3). Type I
changes
defects: mainly septal defects and abnormalities of the cardiac outflow tract • Cardiac problems: hypoglycemia, hypercalcemia • Metabolic contractures • Joint • Osteopenia/bone fractures
3
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Table 3 Characteristic of advanced therapeutic specific SMN dependent approaches under clinical investigation in SMA. Nusinersen (Spinraza®)
AVXS-101 (ZolgenSMA®)
RG7916 (Risdiplam®)
Type of therapy
Antisense oligonucleotide specific to ISSN1 in intron 7 ASO–ISSN1
Pyridazine derivative that increase binding of exon 7 with U1snRNP
Intracellular place of action Mechanism of action
Pre-mRNA in nuclei to include exon 7 Increase amount of complete SMN protein from SMN2
Administration route Dose and frequency of administration Target Type of SMA patients treated
Intrathecally (IT) Four loading doses (12 mg each) and maintenance every 4 months Motor neurons and other CNS cells Type I and II and presymptomatic (Nurture) ongoing
Self-complementary adeno associated virus with human coding SMN1 scAAV9.CB.SMN1 Incorporates in nuclei as episomes Production of SMN protein from SMN1 Intravenously One dose of 2.014 vg/kg
Number of patients treated
Clinical trials 285 Expanded access program 843 Prescription >8000 The majority of AEs and SAEs consistent with the nature and frequency of events typically occurring in the context of SMA or lumbar puncture procedure FDA all SMA types (Dec 2016) EMA (June 2017)
Safety Approval
All non-dividing cells of the organism Type I (type II IT) and presymptomatic (Sprint) ongoing Around 150 (type I-type II) Elevations in ALT/AST in some patients, treatable with prednisolone Unknown long-term safety profile FDA (type I - May 2019) Expanded CTs ongoing
Pre-mRNA in nuclei to include exon 7 Increase amount of complete SMN protein from SMN2 Oral 5 mg/day or 0.25 mg/kg All cells of the organism Type I-type II-type III and presymptomatic (Rainbowfish) ongoing Around 200 (type I, II, III) Favorable safety profile to date Monitoring eye changes based on preclinical data with similar compound CTs ongoing
for SMA which, in fact, may be not opposite but potentially complementary(Table 3). Other medications, SMN independent, are under investigation in SMA such as neuroprotectors, neuromuscular junction stabilizers and muscle function activators (www.clinicaltrials.gov) and it is possible that once the efficacy of all of these compounds is proven, combinatorial approaches with SMN tailored therapies may be investigated and protocolized [29].
patients live longer with motor milestones never observed previously in these patients. However, some complications may appear such as scoliosis, hip dislocation or foot deformities as part of the evolving phenotypes [29]. Motor improvement in some patients may not be clearly observed because are no responders or become responders later [5]. Patients involved in both, ENDEAR and CHERISH CTs are currently followed up in another trial (SHINE, NCT02594124). An open-label CT in pre-symptomatic patients with two (n = 15) and three (n = 10) SMN2 copies starting treatment before 6 weeks of age is also currently ongoing (NURTURE, NCT02386553). The interim analysis in May 2019 indicated that all children were alive, without permanent ventilation and had reached the sitting position. The majority of patients of this CT after at least two years of treatment are able to stand alone and walk independently [30,31]. Personal individual cases treated pre-symptomatically have been presented or reported in several meetings and also confirm the treatment success [28]. The second program started in 2014 and consisted in the single intravenous injection of systemic-delivered AAV9 with the coding part of SMN1 as gene therapy (AVXS-101) to replace defective SMN1 in 15 infants with SMA type I [6,32]. All patients are alive without requiring permanent mechanical ventilation and improving motor milestones [33]. AVXS-101 (Onasemnogene Abeparvovec-xioi, ZolgenSMA®) has been recently approved in May 2019 by FDA for patients <2 years with type I SMA and is currently under review by the EMA. At present this gene therapy treatment is considered the most expensive medication in the world [34]. Studies are ongoing with ZolgenSMA treating diverse population of patients and include a larger population of type I SMA patients (STR1VE, NCT03306277; STR1VE EU, NCT03461289) as well as type II for a single intrathecal injection (STRONG, NCT03381729) and pre-symptomatic cases under of 6 weeks for single intravenous dose (SPR1NT, NCT03505099). As in the case of nusinersen/Spinraza® there is substantial evidence that when gene therapy is initiated early, there is better motor response and respiratory outcomes [32,33]. Other experimental therapies, including for example oral medications that also increase the inclusion of exon 7 are under clinical investigation. The oral compound RG7916 or Risdiplam® is a splicing modifier which is currently in phase 3 in SMA type I patients (FIREFISH, NCT02913482), type II-III patients (SUNFISH, NCT02908685) and pre-symptomatic babies (RAINBOWFISH, NCT03779334) (www. clinicaltrials.gov). Table 3 summarizes the mechanism of action, application and main characteristics of these three main advanced SMN dependent therapies
5. Conclusions: towards expedite diagnosis and early intervention Several conclusions can be formulated in view of published investigations available and sustained data that is permanently increasing and updated in the ongoing clinical trials and real world evidence. First, there is a changing/evolving phenotype in all patients treated and some patients may not be responders, are slow responders or becoming responders after several months of treatment [29]. Second, although medication has demonstrated efficacy, patients with severe SMA are fragile, very compromised and may also die as happened with some patients in the ENDEAR trial. For best results of therapy, patients need a closer follow up with the consensus standards of care in the context of a multidisciplinary team [35,36]. Third, the disease duration prior to treatment as well as the age of initiation of treatment of the patients appear to be strong predictors of efficacy [5,28,33]. There is a rapid progression of SMA1 and a delay in treatment would likely impact the evolution with a greater irreversible loss of function and reduced motor response. Thus, it is important to promote awareness for early detection of the disease and expedite diagnosis. Given the encouraging results of different therapies investigated, and because there is evidence that early intervention and treatment is associated with better prognosis and evolution there is now strong consensus that newborn screening (NBS) should be implemented as secondary prevention of SMA [37]. Facing this new scenario of gradual implementation of SMA NBS, it is envisaged that most of the neonates with SMA will be genetically diagnosed at a presymptomatic stage [37]. This would allow recollection and registry of baseline data and search for clinical manifestations of each patient (as compiled in Table 2) together with information on functional scales such as Children´s Hospital of Philadelpia Infant Test of Neuromuscular Disorders (CHOP INTEND) and on electromyography such as compound muscle action potential (CMAP) or motor unit number estimation (MUNE). The number of SMN2 copies could be used as an initial predictor of SMA type albeit it is of no proven value as a surrogate marker of ongoing disease activity or response to treatment [15]. In this matter, other promising 4
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biomarkers such as phosphorylated neurofilament heavy chain (pNFeH) levels in plasma of SMA patients are under investigation [38]. Communication of diagnosis as well as adequate genetic counselling have to evolve considering that the trajectory of the disease is now changing due to the success of novel therapies to improve motor function in these patients [37]. Shared decision making for treatment and psychological support of the families are critical to cope with the impact of the disease. High cost of these treatments and different health insurances according to countries raises also concerns about access and equity that should be considered. The concept of SMA as an untreatable disease has now fundamentally changed with potential life-transforming therapies, creating new expectations and challenges for patients, families and health care providers.
[16]
[17] [18]
[19]
[20]
Acknowledgments
[21]
The author is indebted to all SMA families and working colleagues and is recipient of Daniel Bravo Foundation and supported by the Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and cofunded with ERDF funds (Grant No. FIS PI18/000687) for SMA research grants.
[22] [23]
[24]
Declaration of competing interest
[25]
The author has received grant support to conduct clinical trials on SMA from Ionis/Biogen and serves as a consultant to Biogen, AveXis, Roche, Biologix, and Cytokinetics.
[26]
References
[27]
[1] Tizzano EF. Advanced therapies in rare diseases: the example of spinal muscular atrophy. Med Clin (Barc). 2018 Oct 12;151(7):275–277. doi:https://doi.org/10.1016/j. medcli.2018.03.001. Epub 2018 Apr 21. English, Spanish. PubMed PMID: 29685310. [2] E.A. Sugarman, N. Nagan, H. Zhu, V.R. Akmaev, Z. Zhou, E.M. Rohlfs, K. Flynn, B.C. Hendrickson, T. Scholl, D.A. Sirko-Osadsa, et al., Pan-ethic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of > 72,400 specimens, Eur. J. Hum. Genet. 20 (2012) 27–32. [3] V. Dubowitz, Ramblings in the history of spinal muscular atrophy, Neuromuscul. Disord. 19 (1) (2009 Jan) 69–73. [4] S. Lefebvre, L. Bürglen, S. Reboullet, O. Clermont, P. Burlet, L. Viollet, B. Benichou, C. Cruaud, P. Millasseau, M. Zeviani, et al., Identification and characterization of a spinal muscular atrophy-determining gene, Cell 80 (1995) 155–165. [5] R.S. Finkel, E. Mercuri, B.T. Darras, A.M. Connolly, N.L. Kuntz, J. Kirschner, et al., ENDEAR study group. Nusinersen versus sham control in infantile-onset spinal muscular atrophy, N. Engl. J. Med. 377 (2017) 1723–1732. [6] J.R. Mendell, S. Al-Zaidy, R. Shell, W.D. Arnold, L.R. Rodino-Klapac, T.W. Prior, et al., Single-dose gene-replacement therapy for spinal muscular atrophy, N. Engl. J. Med. 377 (2017) 1713–1722. [7] T. Munsat, K. Davies, International SMA consortium meeting (26-28 June 1992, Bonn, Germany), Neuromuscul. Disord. 2 (1992) 423–428. [8] R.S. Finkel, M.P. McDermott, P. Kaufmann, B.T. Darras, W.K. Chung, D.M. Sproule, et al., Observational study of spinal muscular atrophy type I and implications for clinical trials, Neurology 83 (2014) 810–817. [9] S.J. Kolb, C.S. Coffey, J.W. Yankey, K. Krosschell, W.D. Arnold, S.B. Rutkove, K.J. Swoboda, S.P. Reyna, A. Sakonju, B.T. Darras, R. Shell, et al., Natural history of infantile-onset spinal muscular atrophy, Ann. Neurol. 82 (6) (2017 Dec) 883–891. [10] K. Talbot, E.F. Tizzano, The clinical landscape for SMA in a new therapeutic era, Gene Ther. 24 (2017) 529–533. [11] S. Lefebvre, P. Burlet, Q. Liu, S. Bertrandy, O. Clermont, A. Munnich, G. Dreyfuss, J. Melki, Correlation between severity and SMN protein level in spinal muscular atrophy, Nat. Genet. 16 (3) (1997 Jul) 265–269. [12] C. Soler-Botija, I. Cuscó, L. Caselles, E. López, M. Baiget, E.F. Tizzano, Implication of fetal SMN2 expression in type I SMA pathogenesis: protection or pathological gain of function? J. Neuropathol. Exp. Neurol. 64 (2005) 215–223. [13] L. Alías, S. Bernal, P. Fuentes-Prior, M.J. Barceló, E. Also, R. Martínez-Hernández, F.J. Rodríguez-Alvarez, Y. Martín, E. Aller, E. Grau, A. Peciña, et al., Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene, Hum. Genet. 125 (2009) 29–39. [14] C.L. Lorson, E. Hahnen, E.J. Androphy, B. Wirth, A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy, Proc. Natl. Acad. Sci. U. S. A. 96 (11) (1999 May 25) 6307–6311. [15] M. Calucho, S. Bernal, L. Alias, F. March, A. Venceslá, F.J. Rodríguez-Álvarez, E. Aller, R. Fernández, S. Borrego, J.M. Millán, et al., Correlation between SMA type
[28] [29] [30]
[31]
[32]
[33]
[34] [35]
[36]
[37]
[38]
5
and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2,834 reported cases, Neuromuscul. Disord. 28 (2018) 208–215. S. Bernal, E. Also-Rallo, R. Martínez-Hernández, L. Alías, F.J. Rodríguez-Alvarez, J.M. Millán, C. Hernández-Chico, M. Baiget, E.F. Tizzano, Plastin 3 expression in discordant spinal muscular atrophy (SMA) siblings, Neuromuscul. Disord. 21 (6) (2011 Jun) 413–419. E.F. Tizzano, D. Zafeiriou, Prenatal aspects in spinal muscular atrophy: from early detection to early presymptomatic intervention, Eur. J. Paediatr. Neurol. 22 (6) (2018 Nov) 944–950. P. Burlet, C. Huber, S. Bertrandy, M.A. Ludosky, I. Zwaenepoel, O. Clermont, J. Roume, A.L. Delezoide, J. Cartaud, A. Munnich, S. Lefebvre, The distribution of SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy, Hum. Mol. Genet. 7 (12) (1998 Nov) 1927–1933. M.G. Boza-Morán, R. Martínez-Hernández, S. Bernal, K. Wanisch, E. Also-Rallo, A. LeHeron, L. Alías, C. Denis, M. Girard, J.K. Yee, E.F. Tizzano, R.J. Yáñez-Muñoz, Decay in survival motor neuron and plastin 3 levels during differentiation of iPSCderived human motor neurons, Sci. Rep. 5 (2015) 11696. C.J. Sumner, Crawford TO, Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain, J. Clin. Invest. 128 (8) (2018 Aug 1) 3219–3227. G. Hamilton, T. Gillingwater, Spinal muscular atrophy: going beyond the motor neuron, Trends Mol. Med. 19 (2013) 40–50. M. Shababi, C.L. Lorson, S.S. Rudnik-Schöneborn, Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J. Anat. 224 (1) (2014 Jan) 15–28. Mendonça RH, Rocha AJ, Lozano-Arango A, Diaz AB, Castiglioni C, Silva AMS, Reed UC, Kulikowski L, Paramonov I, Cuscó I, Tizzano EF, Zanoteli E. Severe brain involvement in 5q spinal muscular atrophy type 0. Ann Neurol. 2019 Jul 13. doi: https://doi.org/10. 1002/ana.25549. [Epub ahead of print] PubMed PMID: 31301241. K.D. Foust, X. Wang, V.L. Mcgovern, L. Braun, K. Adam, A.M. Haidet, et al., Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN, Nat. Biotechnol. 28 (2010) 271–274. Y. Hua, K. Sahashi, F. Rigo, G. Hung, G. Horev, C.F. Bennett, A.R. Krainer, Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model, Nature 478 (7367) (2011 Oct 5) 123–126. N.A. Naryshkin, M. Weetall, A. Dakka, J. Narasimhan, X. Zhao, Z. Feng, K.K. Ling, G.M. Karp, H. Qi, M.G. Woll, et al., Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy, Science 345 (6197) (2014 Aug 8) 688–693. E. Mercuri, B.T. Darras, C.A. Chiriboga, J.W. Day, C. Campbell, A.M. Connolly, et al., CHERISH study group. Nusinersen versus sham control in later-onset spinal muscular atrophy, N. Engl. J. Med. 378 (2018) 625–635. T. Gidaro, L. Servais, Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps, Dev. Med. Child Neurol. 61 (1) (2019 Jan) 19–24. E.F. Tizzano, R.S. Finkel, Spinal muscular atrophy: a changing phenotype beyond the clinical trials, Neuromuscul. Disord. 27 (2017 Oct) 883–889. E. Bertini, W.-L. Hwu, S.P. Reyna, W. Farwell, S. Gheuens, P. Sun, Z.J. Zhong, D. De Vivo, et al., Efficacy and safety of nusinersen in infants with presymptomatic spinal muscular atrophy (SMA): interim results from the NURTURE study, Eur. J. Paediatr. Neurol. 21 (2017 Jun 1) e14. De Vivo, D.; Bertini, E.; Swoboda, K.J.; et al., Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study Neuromusc DIsord (in press) DOI: https:// doi.org/10.1016/j.nmd.2019.09.007. S. Al-Zaidy, A.S. Pickard, K. Kotha, L.N. Alfano, L. Lowes, G. Paul, K. Church, K. Lehman, D.M. Sproule, O. Dabbous, B. Maru, K. Berry, W.D. Arnold, J.T. Kissel, J.R. Mendell, R. Shell, Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy, Pediatr. Pulmonol. 54 (2) (2019 Feb) 179–185. Lowes LP, Alfano LN, Arnold WD, Shell R, Prior TW, McColly M, Lehman KJ, Church K, Sproule DM, Nagendran S, Menier M, Feltner DE, Wells C, Kissel JT, AlZaidy S, Mendell J. Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose Gene replacement therapy. Pediatr Neurol. 2019 May 13. pii: S0887 8994(19)30280–2. https://www.npr.org/sections/health-shots/2019/05/24/725404168/at-2-125million-new-gene-therapy-is-the-most-expensive-drug-ever?t=1565638635392. E. Mercuri, R.S. Finkel, F. Muntoni, B. Wirth, J. Montes, M. Main, E.S. Mazzone, M. Vitale, B. Snyder, S. Quijano-Roy, et al., Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care, Neuromuscul. Disord. 28 (2) (2018 Feb) 103–115. R.S. Finkel, E. Mercuri, O.H. Meyer, A.K. Simonds, M.K. Schroth, R.J. Graham, J. Kirschner, S.T. Iannaccone, T.O. Crawford, S. Woods, F. Muntoni, B. Wirth, J. Montes, M. Main, E.S. Mazzone, M. Vitale, B. Snyder, S. Quijano-Roy, E. Bertini, R.H. Davis, Y. Qian, T. Sejersen, SMA Care group, Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics, Neuromuscul. Disord. 28 (3) (2018 Mar) 197–207. Serra-Juhe C, Tizzano EF. Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors. Eur. J. Hum. Genet. 2019 May 3. doi:https://doi.org/10.1038/s41431-0190415-4. [Epub ahead of print] Review. PubMed PMID: 31053787. B.T. Darras, T.O. Crawford, R.S. Finkel, E. Mercuri, D.C. De Vivo, M. Oskoui, E.F. Tizzano, M.M. Ryan, F. Muntoni, G. Zhao, J. Staropoli, A. McCampbell, M. Petrillo, C. Stebbins, S. Fradette, W. Farwell, C.J. Sumner, Neurofilament as a potential biomarker for spinal muscular atrophy, Ann. Clin. Transl. Neurol. 6 (5) (2019 Apr 17) 932–944.