//概要//---
脊髄性筋萎縮症は脊髄と脊髄上部にある脳幹の運動系の神経細胞のSMNタンパク質量が
低下する疾患です。このたんぱく質の不足によって神経細胞のmRNAの機能に関わる
スプライシングの異常に関連し、運動系神経細胞死につながると考えられています。
その中でⅠ型は重症型、急性で発症が生後6か月迄とされています。
発症後は基礎的な運動に関わる体幹を動かすことも難しくなります。
治療が行われない場合においては2年を超えて生存する事が難しいとされています(2-4)。
Ⅰ型脊髄性筋萎縮症に対して
現状では3つの薬物治療がFDAによって承認されています
そのうちの以下、２つについては一定の効果が確認されています(5,6)。
1: Nusinersen,
SMN2-targeting antisense oligonucleotide,
2: Onasemnogene abeparvovec-xioi、
An intravenously administered
adeno-associated virus vector–based gene-replacement therapy,
いずれも異常が生じているSMN1遺伝子に働きかける遺伝子治療ですが、
運動ニューロンは細胞分裂しないために
一旦、細胞内に遺伝子が導入されるとその効果は持続性を持つと考えられています。
2020年10月5日のロシュ、中外製薬のプレスリリースによると
Ⅰ型脊髄性筋萎縮症の乳児を対象にリスジプラムを評価したところ
17/22名において2年間、継続して運動機能が改善している事を示しました。
88%の乳児が生存し、人工呼吸器の永続的な使用を必要としないことが示されました。
このリスジプラムは薬物治療のうち上述した2つに続き、3つ目の薬剤にあたります。
経口投与の薬剤です。
B.T. Darraら医療研究グループによって行われた非盲検研究の結果(1)では
1か月から7か月の乳児に対して治療を開始して
治療後12か月の時点での運動評価をしたところ、
5秒以上支援なしで座る事が出来た乳児は29%
この運動機能は運動機能スケールスコア(CHOP-INTEND)と関連性があり
1名を除くほぼすべての子供において運動機能スケールの向上が見られています。
人工呼吸器が必要のない治療後12カ月時点の生存率は85%となっています。
しかしながら、重篤な副作用は59%の子供が経験しており
副作用として多いのが上部呼吸器感染症68％となっています。
続いて、肺炎、発熱が39%です。
従って、(風邪)コロナウィルスやインフルエンザのような
呼吸器に関わる感染症のリスクが高まると考えられます。
基本的にこのような副作用は免疫機能と関連があると考えられますが、
これらの乳児に対する授乳の状況はどうであったか？
この情報は副作用において重要な可能性があります。
なぜなら、ウィルスに対してデコイ機能がある
多様なオリゴ糖が母乳の中に含まれているからです。
また、薬理と免疫機能の関連についても調査が必要です。
しかしながら、アデノウィルスによる薬物
Onasemnogene abeparvovec-xioiにおいても
同じように気管支のウィルス性炎症の副作用が報告されています(6)。
薬物そのものが血液中の免疫細胞に働きかけるのか
授乳の有無の影響なのか
神経系の命令を介した異常なのか
元々呼吸器系の運動機能が低下している事が原因なのか
それらの複合的要因なのかという疑問があります。
一方、脊髄性筋萎縮症のSMNタンパク質の不足による脾臓、リンパ節の重篤な異常がマウスのケースで確認されています。従って、有害事象は治療の有無に関係なく生じている可能性があります。
//Background(1)//---
Spinal muscular atrophy is one the most frequent mortality and
gene-related diseases in infant, and 8.5-10.3 of 10,0000 children are affected
with spinal muscular atrophy epidemiologically. The children affected with this
disease can not keep homeostasis of motor neuron due to SMI1 mutation which
results to decrease SMN protein and impair mRNA splicing. As clinical symptom,
respiratory and swallowing function decline and they need to receive feeding
and ventilatory support by 12 months of age(4). Most of untreated infants
cannot survive beyond 2 years(2-4). As spinal muscular atrophy is SMN gene
related disease, gene therapy is the main candidates. Currently, following
three treatment(#1-3) have been approved by FDA against spinal muscular
atrophy.
(#1): Nusinersen- An intrathecally
administered SMN2-targeting antisense oligonucleotide(5)
(#2): Onasemnogene abeparvovec-xioi- An intravenously
administered adeno-associated virus vector-based gene-replacement therapy(6)
(#3): Risdiplam- An orally administered
small molecule drug, which promotes the “Inclusion” of exon7(typically exclusion of exon7 in SMA diseases), by which
SMN2 mRNA level and SMN protein increases(7). In this Letter, I refer to a part
of contents in the open-label study of Risdiplam for the children. This drug is
small molecule, so it could penetrate the blood brain barrier.
Basil
T. Darras, M.D., Riccardo Masson, M.D., Maria Mazurkiewicz-Bełdzińska, M.D.,
Kristy Rose, Ph.D., Hui Xiong, M.D., Edmar Zanoteli, M.D., Giovanni Baranello,
M.D., Ph.D., Claudio Bruno, M.D., Ph.D., Dmitry Vlodavets, M.D., Yi Wang, M.D.,
Ph.D., Muna El-Khairi, Ph.D., Marianne Gerber, Ph.D., Ksenija Gorni, M.D.,
Ph.D., Omar Khwaja, M.D., Ph.D., Heidemarie Kletzl, Ph.D., Renata S. Scalco,
M.D., Ph.D., Paulo Fontoura, M.D., Ph.D., and Laurent Servais, M.D., Ph.D. for
the FIREFISH Working Group* conduct an open-label study for the clinical outcome
of risdiplam for the children with Type 1 progressive spinal muscular
atrophy(1). I hope to share a part of contents and my original discussion with
the global important readers.
//Condition(1)//---
*Place: 14 centers in 10 countries
*Eligibility criteria: 5q SMA (Genetic
condition) / Type 1 SMA / Two copies of SMN2
*Age: 1 to 7 months
*Excluded criteria: Invasive ventilation /
awake noninvasive ventilation / tracheostomy / already received treatment other
SMN2-targeting therapies or gene therapy.
-
* Risdiplam Administration condition
A dose 0.2mg per kilogram of body weight
per day for older than 5 months
For infant younger than 5 months, dose is
adjusted (See (1) Study procedures)
//Result(1)//---
Efficacy at Month 12
*Able to sit without support for ≧5 sec : 29%
(Motor function score)
CHOP-INTEND score of ≥40: 56%
This score continues to increase up to 12
months. (See Figure. S3)
*HINES2- motor milestone (Special note)
The
motor function with physical burden like lifting heat (not 85%), legs (not 59%)
is difficult (See Table. S5). Therefore, gradual and continuous gradual
rehabilitation in careful observation by medical staffs is needed.
*Event-free(not permanent ventilation)
survival: 85%
Therefore, we can evaluate the improvement of
motor function through the gene therapy by Risdiplam.
//Adverse event(1)//---
*At least 1 adverse event: 100%
*At least 1 serious adverse event: 59%
(Most common adverse events)
*Upper respiratory tract infection: 68%
*Pneumonia: 39%
*Pyrexia: 39%
(Most common serious adverse events)
*Pneumonia: 32%
From
the 3 major adverse events, immune system of respiratory system may be
disturbed. Whether severe pneumonia is trigged by upper respiratory tract
infection or not needs to be discussed. And breastfeeding highly affects immune
system of infant. Confirming the fact whether breastfeeding is taken or not is
needed. The study about the relation between immune system and Risdiplam
including in vitro may be valuable. There is the report about the relation between
immune dysregulation and spinal muscular atrophy (SMA) in mice model(8). SMN
protein depletion led to severe alteration in the thymus and spleen related to
immune development. Therefore, analysis in immune landscape and histology
and/or function of these organs in the children with SMA is further needed. The
infant is in the crucial developmental stage of the whole bodies including
neurodevelopment and immune system. Therefore, long-term analysis, treatment
and management are a prerequisite for the improvement of quality-of-life of the
patients and the family in line with the impairment of neurodevelopment and
immune development.
//The other clinical perspective//---
The
SMN protein supplementation plus the gene therapy may have room to be considered.
However, this method may trigger immune system excessively. On the other hand,
the amount of SMN protein and the timing(swiftness) can be controlled more
easily than the gene therapy. The amount of SMN protein may need to be analyze
from biomarker. That is because SMN protein may involve not only “In the neuron”, but also the other organ and
immune system “Out of cell”.
//Support(1)//---
Supported by F. Hoffmann–La Roche.
//Special note(1)//---
The study was approved by an ethics
committee at each study site and was conducted in accordance with the
principles of the Declaration of Helsinki and Good Clinical Practice guidelines
described in the protocol.
//Acknowledgement(1)//---
We thank the staff of the Spinal Muscular
Atrophy Foundation and PTC Therapeutics for their collaboration; all the
patients and families who participated in the risdiplam program; the staff of
the clinical study sites around the world for their ongoing partnership and
assistance; and Lindsey Weedon of MediTech Media for medical writing assistance
with an earlier version of the manuscript, funded by F. Hoffmann–La Roche, in
accordance with Good Publication Practice guidelines
(http://www.ismpp.org/gpp3. opens in new tab).
(Reference)
(1)
Basil T. Darras, M.D., Riccardo Masson,
M.D., Maria Mazurkiewicz-Bełdzińska, M.D., Kristy Rose, Ph.D., Hui Xiong, M.D.,
Edmar Zanoteli, M.D., Giovanni Baranello, M.D., Ph.D., Claudio Bruno, M.D.,
Ph.D., Dmitry Vlodavets, M.D., Yi Wang, M.D., Ph.D., Muna El-Khairi, Ph.D.,
Marianne Gerber, Ph.D., Ksenija Gorni, M.D., Ph.D., Omar Khwaja, M.D., Ph.D.,
Heidemarie Kletzl, Ph.D., Renata S. Scalco, M.D., Ph.D., Paulo Fontoura, M.D.,
Ph.D., and Laurent Servais, M.D., Ph.D. for the FIREFISH Working Group*
Risdiplam-Treated Infants with Type 1
Spinal Muscular Atrophy versus Historical Controls
The New England Journal of Medicine 2021;
385:427-435
---
Author Affiliations
From the Department of Neurology, Boston
Children’s Hospital, Harvard Medical School, Boston (B.T.D.); the Developmental
Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (R.M.,
G.B.), and the Center of Translational and Experimental Myology, IRCCS Istituto
Giannina Gaslini, Genoa (C.B.) — both in Italy; the Department of Developmental
Neurology, Medical University of Gdańsk, Gdańsk, Poland (M.M.-B.); the
Paediatric Gait Analysis Service of New South Wales, the Children’s Hospital at
Westmead and the University of Sydney, Sydney (K.R.); the Department of
Pediatrics, Peking University First Hospital, Beijing (H.X.), and Children’s
Hospital of Fudan University, Shanghai (Y.W.) — both in China; the Department
of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo (E.Z.);
the Dubowitz Neuromuscular Centre, National Institute for Health Research Great
Ormond Street Hospital Biomedical Research Centre, University College London
Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital
for Children NHS Foundation Trust, London (G.B.), Roche Products, Welwyn Garden
City (M.E.-K.), and the Muscular Dystrophy UK Oxford Neuromuscular Centre, the
Department of Paediatrics, University of Oxford, Oxford (L.S.) — all in the
United Kingdom; Russian Children Neuromuscular Center, Veltischev Clinical
Pediatric Research Institute, Pirogov Russian National Research Medical
University, Moscow (D.V.); Pharma Development, Safety (M.G.), Product
Development Medical Affairs — Neuroscience and Rare Disease (K.G., P.F.), and
Pharma Development Neurology (R.S.S.), F. Hoffmann–La Roche, and Roche
Pharmaceutical Research and Early Development, Roche Innovation Center Basel
(O.K., H.K.) — both in Basel, Switzerland; the Division of Child Neurology,
Centre de Références des Maladies Neuromusculaires, the Department of
Pediatrics, University Hospital Liege, University of Liege, Liege, Belgium
(L.S.); and I-Motion, Institut de Myologie, Assistance Publique Hôpitaux de
Paris, Hôpital Armand Trousseau, Paris (L.S.).
(2)
Mercuri E, Bertini E, Iannaccone ST.
Childhood spinal muscular atrophy:
controversies and challenges.
Lancet Neurol 2012; 11: 443-52.
(3)
Munsat TL, Davies KE.
International SMA consortium
meeting
(26-28
June 1992, Bonn, Germany). Neuromuscul Disord 1992; 2: 423-8.
(4)
Finkel RS, McDermott MP, Kaufmann P, et al.
Observational study of spinal muscular
atrophy type I and implications for clinical trials.
Neurology 2014; 83: 810-7.
(5)
Finkel RS, Mercuri E, Darras BT, et al.
Nusinersen versus sham control in infantile-onset
spinal muscular atrophy.
N Engl J Med 2017; 377: 1723-32.
(6)
Mendell JR, Al-Zaidy S, Shell R, et al.
Single-dose gene-replacement therapy for
spinal muscular atrophy.
N Engl J Med 2017; 377: 1713-22.
(7)
Ratni H, Ebeling M, Baird J, et al.
Discovery of risdiplam, a selective
survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of
spinal muscular atrophy (SMA).
J Med Chem 2018; 61: 6501-17.
(8)
Marc-Olivier Deguise, Yves De Repentigny,
Emily McFall, Nicole Auclair, Subash Sad, Rashmi Kothary
Immune dysregulation may contribute to
disease pathogenesis in spinal muscular atrophy mice
Human Molecular Genetics, Volume 26, Issue
4, 15 February 2017, Pages 801–819
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