Translational Research in Muscular Dystrophy

202 Pages·2016·5.029 MB·English

by  Shin'ichi Takeda, Yuko Miyagoe-Suzuki, Madoka Mori-Yoshimura (eds.)

Translational
Research in
Muscular Dystrophy
Shin’ichi Takeda
Yuko Miyagoe-Suzuki
Madoka Mori-Yoshimura
Editors
123
Translational Research in Muscular Dystrophy
ThiSisaFMBlankPage
Shin’ichi Takeda (cid:129) Yuko Miyagoe-Suzuki (cid:129)
Madoka Mori-Yoshimura
Editors
Translational Research
in Muscular Dystrophy
Editors
Shin’ichiTakeda YukoMiyagoe-Suzuki
NationalInstituteofNeuroscience NationalInstituteofNeuroscience
Kodaira,Tokyo Kodaira,Tokyo
Japan Japan
MadokaMori-Yoshimura
NationalInstituteofNeuroscience
Kodaira,Tokyo
Japan
ISBN978-4-431-55677-0 ISBN978-4-431-55678-7 (eBook)
DOI10.1007/978-4-431-55678-7
LibraryofCongressControlNumber:2015957591
SpringerTokyoHeidelbergNewYorkDordrechtLondon
©SpringerJapan2016
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Preface
Since identification of the DMD (dystrophin) gene as the cause of Duchenne
muscular dystrophy (DMD) in 1987, many genes have been found to contribute
tomuscular dystrophies. In particular,recentnext-generation sequencing technol-
ogy has accelerated the identification of disease-causing genes, especially for
α-dystroglycanopathies.Inparallel,newresearchtoolsforrevealingthemolecular
and cellular mechanisms of muscular dystrophies have been extensively investi-
gated,andnewtherapeuticstrategiesfortreatmentofmusculardystrophy,suchas
exonskippingtherapyusingantisense-oligonucleotidesorstemcell-basedtherapy
using pluripotent stem cells, have been proposed. To support development of
therapies and nationwide and international clinical studies for rare, intractable
neuromusculardiseases,theEUstartedtheTREAT-NMDnetworkandtheUnited
Statesstartedacooperativeinternationalneuromuscularresearchgroup(CINRG).
InJapan,apatientregistrysite(registryofmusculardystrophy:REMUDY)(http://
www.remudy.jp/) and a muscular dystrophy clinical trial network (http://www.
mdctn.jp/network.html) were established. These networks actively communicate
with each other to form a worldwide research framework to fight against these
devastatingneuromusculardisorders.
“Translational research” or “translational medicine” means the transfer of
knowledge or technology from bench to bedside, but the interaction should be
bidirectional.Toacceleratethecollaborationbetweenscientistsandclinicians,we
plannedthiseBookandaskedbothtalentedresearchersandclinicalphysicianswho
arecurrentlyworkinginthefieldofmusculardystrophyinJapantocontribute.This
bookcoverscutting-edgestudiesonmusculardystrophies,e.g.,regenerativemed-
icine,next-generationsequencing,andnucleicacidtherapies.Italsodescribesthe
current systems used for clinical trials and patient databases, resources that will
supporttheearlyrealizationofclinicalapplicationandimprovepatients’qualityof
life. Although this eBook might not cover the entire field, we believe that it is
informative and useful to all readers who are interested in the neuromuscular
diseases.
The editors thank all the authors who have contributed to this eBook and all
colleagueswhohelpedustoeditthemanuscripts.WealsoappreciateDr.Kiyohiko
v
vi Preface
TakayamaandMs.TamakiYamamotoatSpringerJapanfortheirhelpinboththe
planningandeditingprocesses.
Tokyo,Japan Shin’ichiTakeda,M.D.,Ph.D.
Onbehalfofalleditorsandauthors
Contents
1 FukuyamaCongenitalMuscularDystrophy:ClinicalAspects. . . . 1
KeikoIshigaki
2 α-Dystroglycanopathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
MotoiKanagawaandTatsushiToda
3 MyotonicDystrophy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
MasayukiNakamoriandMasanoriP.Takahashi
4 MolecularPathogenesisandTherapeuticStrategyinGNE
Myopathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
HiroakiNishimuraandSatoruNoguchi
5 TargetingtheTypeITGF-βReceptorforTreatingCaveolin-3-
DeficientAutosomalDominantLimb-GirdleMuscularDystrophy
Type1CandMuscleWastingDisorders. . . . . . . . . . . . . . . . . . . . . 77
YutakaOhsawa,Shin-ichiroNishimatsu,MasahiroFujino,
andYoshihideSunada
6 TranslationalResearchinNucleicAcidTherapiesforMuscular
Dystrophies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
JoshuaJ.A.LeeandToshifumiYokota
7 TowardRegenerativeMedicineforMuscularDystrophies:
LessonsfromRegenerationProcesses. . . . . . . . . . . . . . . . . . . . . . . 103
AkiyoshiUezumiandSo-ichiroFukada
8 StemCell-BasedTherapyforDuchenneMuscularDystrophy. . . . 123
YukoMiyagoe-SuzukiandShin’ichiTakeda
9 TherapeuticApproachofiPSCellTechnologyforTreating
MuscularDystrophy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
HidetoshiSakurai
vii
viii Contents
10 ClinicalAspectsofGNEMyopathyandTranslationalMedicine. . . 153
MadokaMori-Yoshimura
11 PatientRegistriesforInternationalHarmonizedClinical
Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
EnKimuraandHarumasaNakamura
12 MuscularDystrophyClinicalTrialNetworkinJapan. . . . . . . . . . 179
KatsuhisaOgata
13 TranslationalResearchonDMDinJapan:FromMiceto
ExploratoryInvestigator-InitiatedClinicalTrialinHuman. . . . . . 189
Shin’ichiTakedaandTetsuyaNagata
Chapter 1
Fukuyama Congenital Muscular Dystrophy:
Clinical Aspects
KeikoIshigaki
Abstract Fukuyama congenital muscular dystrophy (FCMD), the second most
commonmusculardystrophyintheJapanesepopulation,isanautosomalrecessive
disordercausedbymutationsinthefukutin(FKTN)gene.FKTNencodesaprotein
involved in the glycosylation of α-dystroglycan (α-DG), which is important for
linkingthebasallaminatocytoskeletalproteinsinmuscles,peripheralnerves,and
the brain. The main features of FCMD are a combination of infantile-onset hypo-
tonia,generalizedmuscleweakness,eyeabnormalities,andcentralnervoussystem
involvementwithmentalretardationandseizuresassociatedwithcorticalmigration
defects. The peak motor function is seen between the ages of 2 and 8 years, and
maximalmotorabilityisusuallyunassistedsittingorslidingonthebuttocks.Most
patients die of respiratory dysfunction, pulmonary infections including aspiration
pneumonia,suffocation,orcongestiveheartfailure.Themeanlifespanislessthan
20years.InmanagingtheFCMDpatients,twocharacteristiccomplicationsshould
beconsidered.Thefirstisfrequentepisodesofketotichypoglycemiaoftenseenin
youngleanpatients.Thesecondissuddensevereexacerbationofmuscleweakness
followingviralinfections,whichcanbefatal.Inthissection,theauthor’sextensive
experience,gainedbymanagingnearly200FCMDpatients,willbedescribed.
Keywords α-Dystroglycanopathy • Fukutin • Rhabdomyolysis • Cobblestone
lissencephaly
1.1 Introduction
Fukuyamacongenitalmusculardystrophy(FCMD),characterizedbythecombina-
tion of severe muscular dystrophy and dysgenesisof the eyes and central nervous
system (CNS) causing intellectual deficits and epilepsy, was first reported by
Fukuyamaetal.in1960[1].FCMDisoneofthemostcommonautosomalrecessive
disorders in Japan and is second in prevalence to Duchenne muscular dystrophy
(DMD)among Japanese childhood-onset progressive muscular dystrophies, while
K.Ishigaki(*)
DepartmentofPediatrics,TokyoWomen’sMedicalUniversity,SchoolofMedicine,
8-1Kawada-cho,Shinjuku-ku,Tokyo162-8666,Japan
e-mail:[email protected]
©SpringerJapan2016 1
S.Takedaetal.(eds.),TranslationalResearchinMuscularDystrophy,
DOI10.1007/978-4-431-55678-7_1