Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. ee nw satasee oclss hycnepesafntoa rti oalvaedsae hshas using This typically cells disease. extracted culture. alleviate the tissue into to a in a Duchenne functional vector introducing a viral and and express a individuals (SMA) affected can from atrophy disrupted they cells the so muscular of progenitor copy cells spinal intact to an performed in deliver transgene, to been a as is as replacement expression, known of gene gene, goal conditions reduced the single-gene (DMD), For or dystrophy muscular disorders. absent neuromuscular life-limiting from treat to resulting avenue new a provides therapy Gene Introduction There therapeutics. DMD. towards neuromuscular and point into SMA aggregate Manuscript with DMD) in which individuals in also horizon, for We the inclusion future on DMD. in hopeful (as in promote mediated a delivery exclusion genetically to novel or splicing microdystrophin promising clinical pre-mRNA multiple SMA) of are alter in from results to SMA work early in in transformative the antisense abeparvovec-xioi (as and the of onasemnogene practice introduction review of We the approval clinical review Administration in gene. application sized and functional its Food smaller a and States and of United duplications introduction to also the trials but by deletions, defect exon to genetic of due the deletions often whole-gene within most variants homozygous disorder disease by recessive mono- muscle caused autosomal fatal typically recessive an are is X-linked is that (DMD) SMA neurons dystrophy . motor muscular loss-of-function affecting Duchenne by caused and disorders (SMA) neuromuscular atrophy genic muscular spinal 5q-linked Both DMD. and SMA with on individuals Abstract therapies for (as mediated future exclusion genetically hopeful or novel a SMA) introduction promising towards in the multiple point nusinersen review are aggregate in There also in (as We which therapeutics. inclusion DMD. horizon, and neuromuscular exon in workthe into SMA promote delivery transformative DMD) in to microdystrophin the in abeparvovec-xioi splicing of eteplirsen review onasemnogene pre-mRNA results in We alter of early approval to gene. the oligonucleotides Administration oppor- functional and antisense Drug exon the practice a of and to offers clinical of Food therapy due in introduction States replacement application often the United Gene its most by to gene. disease defect trials DMD muscle genetic clinical the recessive underlying from within X-linked the variants an correct sized is smaller to typically DMD and tunity is that duplications SMN1. neurons also motor of but affecting neuromuscular deletions deletions, disorder monogenic recessive whole-gene fatal autosomal homozygous an are by is (DMD) SMA caused dystrophy muscular mutations. loss-of-function Duchenne by and caused (SMA) disorders atrophy muscular spinal 5q-linked Both Abstract 2020 1, July 1 Abreu Nicolas and Atrophy Dystrophy Muscular Muscular Spinal Duchenne in Therapy Gene of Overview ainieCide’ Hospital Children’s Nationwide xvivo ex 1 n ea Waldrop Megan and DMD o eaooia n muooia iodr yrmvn eaooei tmand stem hematopoietic removing by disorders immunological and hematological for ee eerpaeetteayoesteopruiyt orc h underlying the correct to opportunity the offers therapy replacement Gene gene. 1 h oli oitgaetetaseeit h otgnm ota when that so genome host the into transgene the integrate to is goal The 1 1 SMN1 M san is DMD . Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. uigps-rncitoa rcsig edn otepouto fmsl ofntoa M protein. SMN nonfunctional mostly of production the from gene, to mRNAs modifying of leading a 10-15% processing, However, of post-transcriptional number copy during by to 7 driven identical largely nearly are is SMA of phenotypes Individual SMA. atrophy. typical muscular from features distinguishing stpclyascae ih2cpe of copies of of 2 copies copies of with number associated the typically to is related inversely is severity phenotypic appearance clinical the mimic may that atrophies muscular described. spinal been non-5q all as have known variants disorders missense to of and group mutations, a site is splice variants, frameshift variants, in variants than SMN1- loss-of-function more thus biallelic proximal and to death. due region, symmetric, infant and is progressive, of cord form cause with spinal common inherited associated the most of The is cells atrophy. and SMN1 horn and brainstem, anterior weakness lower the muscle the of distal degeneration in from nuclei results motor (SMA) atrophy muscular using Spinal therapeutics medicine. neuromuscular novel for exciting ahead some future explore bright DMD, We the and show therapy. SMA to replacement for order therapies gene in mediated well and as genetically ASOs strategies in on alternative progress focus tremendous the a DMD. highlight with and we applicable SMA not review, like are transcript this function but the In disease, of protein Huntington degradation of in promote loss transcript as to mutations, with mature engineered gain-of-function the disease be toxic within of in in also from sites number may expression result exon specific They that change alter to diseases protein. thereby bind in to functional and that more design, strategy nucleotides a their synthetic therapeutic produce on to modified based generate RNA-based splicing of to an oligonu- alter sequences material to short is antisense genetic pre-mRNA are foreign this of ASOs of instead introduction introduction . much but no existing the is is expression, which was there kilobases, therapy, transgene therapeutics gene 5 novel neuromuscular from of Distinct in capacity (ASO). carrying progress cleotides small towards its step is community.Another though the vector in mus- AAV antibodies and AAV9 the an system neutralizing than of nervous common pre-existing smaller use the a of transduce the titers be efficiently to high to to AAV9 limitation of ability leading prevalence its lower population, to and due general cle, therapy the to gene only in cases neuromuscular and antibodies in some disease pre-existing vector human in of with shown prevalence associated system. and been be immune to tropism has innate known which not the cancer. transgene, are activate of which the weakly vectors, risk (AAV) of increased virus integration an adeno-associated of and of lack mutations unwanted the in is host result method the this into for integrate of vantage to considerations where need several individual, without are affected replicate There an and into cells directly enter delivered to and transgene vector the genome. viral allows a so machinery within viral and packaged the after cells, is cells muscle transgene non- daughter long-lived, a replicating their of Here, slower onto transduction requires transgene and conditions the neuromuscular nerve transfer for replicating they therapy gene patient, contrast, the In into engraftment. reintroduced are cells treated the UdrtnigSia uclrAtrophy Muscular Atrophy Spinal Muscular Understanding Spinal 2. in Therapy Gene 1. SMN1- sria oo ern1gn) curn naot8i 0,0 iebrh,i a enteleading the been has it births, live 100,000 in 8 about in Occurring gene). 1 neuron motor (survival eae M ar ooyosdltoso xn7 huhallswt mle eein,nonsense deletions, smaller with alleles though 7, exon of deletions homozygous carry SMA related 1 SMN2. eae ies,btaedet ayohrgntceilge n fe ncoeeauto have evaluation close on often and etiologies genetic other many to due are but disease, related DMD 10,14,15 SMN1- SMN1 gene. eae M a lob eerdt s5 M.Aot9%o niiul with individuals of 94% About SMA. 5q as to referred be also may SMA related 7 ihauiu oTtasto neo htrslsi xlso fexon of exclusion in results that 7 exon in transition T to C unique a with , 9 SMN1 SMN2 nvivo in SMN2 slctdo h ogamo hoooe5 pcfial h 5q13.2 the specifically 5, chromosome of arm long the on located is eaneo n rdc oefl-eghSNprotein. SMN full-length some produce and 7 exon retain 11 3,4 eerpaeetteayi ermsua ies.Oead- One disease. neuromuscular in therapy replacement gene hl dl-ne M stpclyascae ih4o more or 4 with associated typically is SMA adult-onset while , eefe,teueo M ilecuieyrfrt qspinal 5q to refer exclusively will SMA of use the Hereafter, hr r ayAVsrtpsta ie ntrso tissue of terms in differ that serotypes AAV many are There 2 8 nvivo in 2 ao dac a entedevelopment the been has advance major A SMN2 eeteaysrtge r preferred. are strategies therapy gene rsn,weeifnieostSMA infantile-onset where present, SMN2 hsgene This . 12,13 10 There 5,6 The A Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. nat gd17mnh a tlata4pitipoeeti oo ucinn rmbsln ntetotal the on baseline from functioning motor in improvement retinal point demonstrating 4 RG7800 a least modifier at splicing had months related 1-7 a aged infants on monkeys. based cynomolgus effects in off-target of concerns unsupported, sit sit to to able ability of the being copies lose 3-4 toddlerhood, eventually with or and skill, SMN2, infancy that of later lose copies then in 3 mid-twenties. but have onset their treatments. often through symptom 6 directed live They with to two-thirds to walk. prior but prior form, failure to but attenuated respiratory able birth to more not due after but a age onset of is disease years SMA 2 as 1 about classified 2 unassisted. Type and of been sit expectancy complications. age has to life respiratory and a inability upon from have subtypes with life based the age, of of months types of common 6 months into of most first copy the categorized the 1 is within have was well SMA typically dying SMA SMA historically 0 therapies, symptoms, Type with of disease-modifying Children of presentation. of onset severity the to Prior ls fteaetc oAO srsilmmyb ie neal nlqi omdiyisedo requiring of instead protein. daily SMN form full-length liquid of of in 7 enterally production different given a exon in be to is may binds It risdiplam. as molecule, administration. ASOs small intrathecal bioavailable to necessary orally those therapeutics the be in of is may needed class nusinersen sedation be to though may alternative treatment, planning emerging surgical tolerated An advanced well scoliosis. and and anxiety, for safe procedural fusion a with spinal overall doses. baseline those considering is loading at or It four recommended children young of is dose. toxicity in completion each treatment, renal after to life-long and phase a prior maintenance abnormalities is and the coagulation It in walk thrombocytopenia, barrier. year 6-minute for blood-brain per the the Monitoring punctures cross on walk cannot lumbar baseline to ASO three able to the were visit). requiring compared as they final intrathecally when nusinersen, at administered treatment with 377.75 is of age and v. months of meters 10 years 369.5 over 59 (mean amount and test 18 modest between a alone treated by stand SMA further to Though, 3 able Type termination. were with Scale- early who adults children Motor in For of Functional resulting proportion Hammersmith group, the assistance. control the in with the on groups a walk in between survival points or point difference to of ˜4 significant ˜1 due no in likelihood in was increase decrease increased early there a an overall terminated the to was an compared of trial there and Expanded treatment, 2 the response analysis, of Section final weeks, milestone months the on motor 15 7.9 In milestones a of group. months. showed motor control 13 age infants the over in in mean treated improvement 0% of a showing to compared 51% infants at Examination, treated Neurological treated full- Infant of ultimately SMA Hammersmith and (41%) 1 7 percentage Type exon high containing of with transcripts N1 treatment infants of silencer the synthesis in splicing the for from intronic increases protein. (FDA) 7 the SMN nusinersen length exon Administration site, target of the to Drug out at designed splicing and ASO routine Food the modified U.S. suppress 2-methoxyethyl to a the nusinersen, by was approved SMA atrophy muscular first life. spinal of The comprehensive quality of neurodevel- improving cornerstones mobility, and remain health, disease and bone were the care. status, wellness of gastrointestinal psychosocial complications and and Historically, of opment, SMA. nutritional management for function, States on United respiratory focused the Supporting in care therapies of disease-modifying mainstay approved Atrophy no the Muscular were Spinal there 2016, for to options Prior treatment therapy replacement non-gene expectancy. of life Landscape normal a have and of ambulate copies to more or 4 with 20,21 23 hswr a olwdb hs ra fTp M hlrnae - er.After years. 2-9 aged children SMA 2 Type of trial 3 phase a by followed was work This SMN2 22 namlietrpae3rnoie,dul-ln,sa-otoldtilo nusinersen of trial sham-controlled double-blind, randomized, 3 phase multicenter a In 24 29 SMN2 27 ae nitrmaaye fFRFS NT2142,9%o M ye1 Type SMA of 93% (NCT02913482), FIREFISH of analyses interim on Based r-RA ipaighRPpoen n rmtn nlso feo for 7 exon of inclusion promoting and proteins hnRNP displacing pre-mRNA, idpa sacnrlyadprpeal itiue piigmdfirthat modifier splicing distributed peripherally and centrally a is Risdiplam yposbgnatr3 er fae n niiul yial continue typically individuals and age, of years 30 after begin symptoms , 26 27,28 SMN2 idpa a hw ob aei elh outesdespite volunteers healthy in safe be to shown has Risdiplam 19 16 19 25 ye3rfr oidvdaswoaheeteaiiyt walk to ability the achieve who individuals to refers 3 Type n soitdwt omllfsa.FrTp SMA, 4 Type For lifespan. normal a with associated and , hlrnwt ye1SAhv - oisof copies 2-3 have SMA 1 Type with Children uiesnwsapoe yteFAfraltpso SMA of types all for FDA the by approved was Nusinersen SMN2 3 r-RA(al ) ydslcn h hnRNP the displacing By 1). (Table pre-mRNA SMN2 n aenoaa onset neonatal have and SMN2 17,18 Type and Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. hs rasaeudra nteUie tts uoe n atAi,a ela rasepoigpre- exploring trials as well as Asia, East and with functioning) individuals Europe, motor for States, baseline administration low abeparvovec-xioi United onasemnogene more with the intrathecal (also in and months underway outcomes, treatment 7.9 are symptomatic motor at trials in trial improvement 3 the greater Phase functioning. follow-up. in with in long-term patient associated improvement of oldest modest be end the only the may by demonstrated point, age spoke this of and to months safely feeding and three oral than support. partial with indepen- earlier least standing achieved achieved Dosing at patients others tolerated two additional children and two of seconds revealed 30 (11/12) transfer least at post-gene ULN. for individual years 37X sitting two at dent one AST additional and and an ULN, ULN for 35X 10X asymptomatic. Follow-up high-dose at than and ALT the transient less of in were result of elevations individuals a elevations as aminotransferase three had prednisolone All day only Two additional ALT. 1 required with that and starting response, elevations days AST had this 30 in attenuated elevations for manifes- Prednisolone showing mg/kg clinical cohort without 1 transfer. but prednisolone gene ULN with to amino- 14X immunosuppressed alanine prior (AST) were levels, aminotransferase patients aminotransferase least aspartate subsequent serum independently. at elevated and walk tations, significantly for (2x10e14 ULN and have 9 crawl cohort 31X to seconds, (ALT) to high-dose noted 5 transferase was able the least patient were in at first 2 individuals for the and unassisted 12 After over, sit the roll to Of could able 9 age. were seconds, 11 of weight), 30 months body 20 support of at (ventilatory genomes/kilogram controls survival vector event-free history natural had of all SMA physiologic 1 8% and Type to milestones 15 related of motor abeparvovec be onasemnogene in of of may trial copies which escalation two dose 10, with open-label, children mice. day 1/2a, in phase postnatal group AAV9 landmark at when of a the scAAV9-SMN In effect trapping in with little associated days cohort and and 15.5 treated genesis 5, astrocyte the of day postnatal in age postnatal days at median 250 1. treated a than day were demon- from more postnatal genomes 5x10e11 on extended to intravascularly using SMN was replacement administered without gene survival scAAV9 days, and 13 with of outcomes treated lifespan motor typical a excellent with strated model mouse SMA host an for In neurons. waiting intramolec- spinal motor than an of and rather form nature brain to non-replicating strand. virus and of and second recombinant replication transduction the the efficient of robust of synthesis for its region cell-mediated allowing SMA. and coding of DNA, barrier the pathogenesis double-stranded the allows blood-brain ular underlie template the to self-complementary known cross a neurons to of expression. motor alpha gene ability including of its neurons, levels to cord high self-complementary due drive administration a to ideal (IV) (scAAV9) within is intravenous 9 promoter one-time serotype hybrid enhancer/chicken-beta-actin viral a cytomegalovirus involves adeno-associated a treatment of The control the 1). first (Table the FDA of the became by abeparvovec-xioi approved onasemnogene apy 2019, Atrophy May Muscular Spinal In with children for double-blind, Therapy multicenter, a Replacement in Gene old years 25 FDA. to the 2 from with age review NCT02908685). in ranging (SUNFISH, SMA (CHOP-INTEND) study 3 Disorders Type -controlled and Neuromuscular 2 of Type Test with Infant individuals treatment. of of months 16 Hospital after Children’s the of score namto ftedra otgnla hc a o ense nayhmn h a led received already had who humans any in demonstrating seen data been primate not non-human has of which review ganglia, after FDA root the dorsal by the hold of partial inflammation a on remains abeparvovec results. interim couraging SMN SMN2 opeetr N,fo hc ullnt M rti a epoue.Tetaseei under is transgene The produced. be may protein SMN full-length which from DNA, complementary ois(C0559,NT3027 C0418,NT3314 C0312) ihen- with NCT03381729), NCT03837184, NCT03461289, NCT03306277, (NCT03505099, copies 39 SMN2 so ue22,teoe-ae hs /atilo nrtea onasemnogene intrathecal of trial 1/2a phase open-label the 2020, June of As 30 nadto,ipoeeti oo ucinn a ensgetdfrtreated for suggested been has functioning motor in improvement addition, In rae ewe . n . otso g,teewsmre improvement marked was there age, of months 7.9 and 0.9 between treated 34 n-ieamnsrto spsil ae pntelongevity the upon based possible is administration One-time 32,35 4 hr a ata mrvmn nsria hnmice when survival in improvement partial was There 31 38 so ue22,rsilmrmisudrpriority under remains risdiplam 2020, June of As nvivo in 36 < ytmclydlvrdgn ther- gene delivered systemically 6husprdy oprdto compared day) per hours 16 37 38 32 nadto,temajority the addition, In hssrtp fAAV of serotype This 33 h engineering The 37 Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. M scaatrzdb oso muainpirt g 3wietemle om ekrmsua dystrophy, muscular Becker form, milder gene, the while -encoding 13 the age dystrophinopathies, to in X-linked prior of ambulation mutations of spectrum with loss the by associated characterized of diseases is end DMD muscle severe life-limiting the are on is which (DMD) dystrophy muscular Duchenne any at the given completing be after weeks may 4 vaccinations until Inactivated given be transfer. not gene should to vaccines attenuated prior basis maternal live week course. individual passive but prednisolone one of an transfer, least risk on gene weighed at theoretical post time given the be of should be out may benefits transfer and and physician. gene risks treating after the the days however the develop with weeks in may 30 antibodies, 4-6 restricted caregivers anti-AAV9 and when was for exposed, of during, gloves Breastfeeding hygiene If transfer before, hand protective therapies. shedding. AAV9 trial good of viral potential 1 as of future use phase well result from as on a them waste, precluding as counseled and immunity exposures AAV9 are fluids minimize bodily and transfer to patient guardians administration gene with disease, after undergo contact human direct cause who into not infants coming does of abeparvovec-xioi onasemnogene providers close for childcare upon vector based viral adjusted unclear the is of prednisolone Although period. and levels post-treatment dysfunction, also troponin-I liver immediate is underlying the cardiac There no throughout with in monitoring taper. children elevations 2-week treat and to a given and counts under is prednisolone platelet administration of in treatment mg/kg significance. decreases after clinical 1 SMA transient of weeks days 1 of 7 30 Type description biopsy recommended and with the ULN liver completed individual 80X of program. already AST an inflammation access jaundice, after massive with managed injury and injury the liver liver ULN, acute acute 45X developed Onasemnogene response. of ALT the aminotransferases aminotransferases. warning immune elevated elevated instances, AAV9 box and premorbid black some the ( with include normalizing a in suppress effects are side carries further days ALT monitoring; common abeparvovec-xioi 30 most and to vg/kg. ongoing The least AST increased 10e14 on at out. until x spaced be continue for depending 1.1 should recommended to dosing of is monitoring need in and dose laboratory may transfer, a adjustment gene dose at with to minutes prednisolone effects, weaning, prior 60 day cardiac to over one for infusion prior begins monitor IV mg/kg/day via 1 to Prednisolone given treatment is anti-AAV9 after noted. abeparvovec with and been Onasemnogene individuals has baseline toxicity so at cardiac and intervention. clinical levels from no treatment, I excluded although of troponin been efficacy have monitoring 1:50 limit recommends than and greater immunogenicity titers administration. bilirubin, of abeparvovec antibody AST, onasemnogene risk (ALT, to hepatitis prior (HIV), increase laboratories” virus essential may immunodeficiency are transfer testing human serologies) gene of genetic C consideration “SMA and as SMA well B baseline confirmatory as counts, and clinic, platelet titers in time, prothrombin AAV9 or with screen evaluation newborn safety via identified is with individual disease. eligible end-stage an without Once of age minority of a years only 2 in than active less currently is and of slow copies is implementation 2018, maximiz- in thus states. and screening SMA newborn of transfer. for identification program gene early allowing to care, response revolutionized ing has Atrophy SMA Muscular for Spinal screening for Newborn therapy gene of practice clinical The transfer. gene intrathecal UdrtnigDcen uclrDystrophy Muscular Dystrophy Duchenne Muscular Understanding Duchenne 2. in Therapy Gene 1. SMN2 44 SMN2 hl nta lncltil fgn elcmn hrp agtn on nat ihSAwt 2 with SMA with infants young targeting therapy replacement gene of trials clinical initial While oynme hudb opee Fgr ) netegntcdanssi ofimd a confirmed, is diagnosis genetic the Once 1). (Figure completed be should number copy D prvlfroaengn bproe-iiwsgatdfralcide ihSMA with children all for granted was abeparvovec-xioi onasemnogene for approval FDA , 45 5,37,46,47 vrl,oaengn bproe sasf n ihyeetv ramn hncare when treatment effective highly and safe a is abeparvovec onasemnogene Overall, 40 5,37,45 41–43 45 h hl eundt aeiesau fe s fcriotrisadhad and of use after status baseline to returned child The acntosmyb dutda h iceino h raigphysician treating the of discretion the at adjusted be may Vaccinations hl M a nlddi h eomne ..uieslscreening universal U.S. recommended the in included was SMA While 5 37 5 45 h rsrbn nomto also information prescribing The < XUN n hnmybe may then and ULN) 2X 45 lvtdAV titers AAV9 Elevated 37 Weekly DMD 37,45 . Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. edfrsrs-oeseod rudtetm fileso ceue ugre nodrt rvn adrenal prevent to order in surgeries scheduled or possible illness the of of aware and time be striae, the also must acne, around families steroids cataracts, crises. and a side stress-dose hypertension, patients with common Physicians, for reflux, age most occur. need younger the fractures, may even are puberty, all of an appearance delayed dysregulation cushingoid years at stature, behavioral and starting 4-5 short hirsutism to around though gain, benefit recently Weight effects, be growth. more reductions. may linear dose to there in prompt decline, though may reduction motor skills, or of motor regimen. gain dosing in start be weight weekend decline may the on which to at effects prior dosing, initiation less weekend age have from including and evolved suggested, outcomes has been Treatment motor have 1). for regimens (Table beneficial dosing survival equally the alternative prolong reduce and cardiomyopathy, may of effects in and onset side surgery, benefit delay scoliosis showing functioning, first for motor improve DMD, need prodrug, for care a neuromuscular deflazacort, of crux long-standing 1974. Dystrophy the ˜30 Muscular been Duchenne to have for Glucocorticoids DMD options with treatment therapy individuals non-gene of of remains. survival Landscape therapies the median disease-directed address the of to increased importance outcomes. vital have the possible is years, ventilation best care non-invasive the dystrophy ensure and muscular and surgery individuals Multidisciplinary these anxiety. are of population. and needs disorder, general many depression hyperactivity the of attention-deficit to risk compared intellectual and corticosteroid increased like rates by disorder disorders higher complicated tract. spectrum Neurodevelopmental at be gastrointestinal autism seen may the scoliosis. and in disabilities, and common muscle contractures learning are smooth emptying special include disability, density in sequelae gastric mineral this dystrophin delayed Orthopedic of bulbar bone in and low function and use. altered and articles reflux respiratory to obesity of constipation, other related stature, strength with be in Short of may affected, DMD-associated adverse detail loss part also progressive as in more care. is from that well of function in complications as standard Gastrointestinal respiratory explored disease, current the muscles. be of muscle as well part underlying will as as a the defects not edition, as of conduction is used result and this corticosteroids a cardiomyopathy enteral though as long-term out-of-frame, dysfunction from are multisystem phenotype. effects deletions in BMD intragenic milder results deletions. a to DMD in-frame to DMD due with lead severe DMD BMD to incomplete in more with predicted to seen a individuals are lead consistently and deletions) and of function (in-frame 90% production frame residual frame reading About dystrophin rule some reading translational frame absent with translational mRNA reading the production the or preserve in dystrophin the minimal shift that use very a Deletions typically in to Clinicians phenotype. result lead that nucleotides. Deletions deletions) few the predictions. (out-of-frame a within phenotype of in insertions assist more to and or deletions one and of changes, needed. deletions be from may result analysis gene. mRNA dystrophinopathies ˜2-3 muscle of noticed instances first 60-70% rare very are Approximately occur. in Symptoms diagnosis though in age sequencing, maneuver. and delays Gower’s variable analysis significant a with duplication though and described age, toe-walking, been of gait, have years waddling symptoms. births. carriers a of male female enlargement, live severity symptomatic calf 6000 and disorder, to onset recessive 5000 X-linked of in an 1 is about cell in this in infiltration the identified fatty to is muscle and integrity DMD causes fibrosis located structural dystrophin regeneration, is of providing impaired Dystrophin Absence with membrane, all. degeneration complex. plasma at muscle. to glycoprotein not fiber transmembrane leading or muscle instability, associated years membrane the the 16 to after of ambulation bound side of when cytoplasmic loss with the spectrum on phenotypic wide a has 54,55 65 48 hi pcfi ehns fato nDDadeet nBDrmi nnw.Pensn and Prednisone unknown. remain BMD in effects and DMD in action of mechanism specific Their escmo uain nld nrgncdpiain,snl uloievrat,slc site splice variants, nucleotide single duplications, intragenic include mutations common Less 69 eiaintpclycniusidfiieywiemntrn o ieeet,which effects, side for monitoring while indefinitely continues typically Medication 51 al yposo M nld eae rs oo milestones, motor gross delayed include DMD of symptoms Early 56–58 6 52 59,60 64 igoi scnre with confirmed is Diagnosis 66,67 ute,ptet n hi aeiesaeat are caregivers their and patients Further, 49,50 al otcseoduei o without not is use corticosteroid Daily lhuhmlsaemsl ffce as affected mostly are males Although 61–63 lhuhavne iescoliosis like advances Although DMD eeinand deletion DMD 68 53 Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. h ntdSae ihipratdffrne nAVsrtp,pooe,tasee n nlso criteria inclusion promoter, and plus transgene, enhancer promoter, serotype, early AAV CMV in the NCT03368742). differences vector of NCT03362502, important response. (NCT03769116,, poor specificity with immune tissue vector, States the United of the the lack boosted against no have and antibodies in may serotype, neutralizing resulted AAV2.5 which subsequent pre-existing informed to transfer This with due but transgene. challenges uptake microdystrophin established, highlighting the and was by vector AAV Safety trials the akin to protein responses delivery. a T-cell expression. truncated intramuscular detectable microdystrophin internally produce via of functional, to levels patients a domain significant produce 6 C-terminal and in the vector performed AAV mutations. and synthetic an BMD-like designed repeats achieved “in-frame” within have researchers spectrin-like to fit was vectors, may AAV the muscle of that of in capacity transgene carrying many transduction small removing transgene and gene microdystrophins, efficient dystrophin providing vectors, the directly AAV of with size by of seen therapies challenges discovery the emerging the without among With promise the great of . holds copy DMD functional in a therapy Dystrophy replacement Muscular Gene Duchenne with FDA children review. under for this or transfer of investigation Gene scope under FDA. the currently the beyond therapies by are approved steroidal that not review and is technologies, but exon-skipping EMA, benefit. therapies, the a by suggest data Europe registry in of review of and readthrough analyses ribosomal additional induces that of enterally 1). result (Table a administered in as therapy underway. change codons molecule currently catheter stop meaningful is small indwelling premature that distinct of of (NCT02500381) a demonstration risk trial is ESSENCE as and 3 well monitoring phase as scale dystrophin function humans, larger increased in renal the in used showed requesting outcomes (Table been DMD functional rejection, has with initial what PMO, individuals than their 53-skipping 25 dose in exon higher weeks, the 10X 48 was a over DMD with infusions baseline. for to IV FDA compared weekly the expression once by approved With expectation be the 1). to and events ASO adverse treated second no of The expression, 1). majority (Table dystrophin the of benefit marker clinical in surrogate future ambulation the attenuationof improved using expression, and data dystrophin capacity, limited of controls. vital on amount historical forced to significant compared on but all when Clinical small based individuals of catheter. respectively. a decline mutations venous ˜13% demonstrated DMD central respiratory variants, all have implanted of of an PMO of 7.7% via and the number typically 8.1% weekly, of up large infusion trials making IV the sites 53, by amenable applicable and Despite administered most 45 with is third exon and individuals Eteplirsen at 52). second are in The skipping exon frame exon mutations. single skipping-amenable or reading for 51 the 48-50 exon bear restores exons DMD improve with and and of individuals phosphorodiamidate nucleases exclusion deletions from a 51 degradation (e.g., avoid reading exon as to mutations promotes the sugar known It ribose restore otherwise the affinity. may to ASO, target modifications exon has morpholino one that dystrophin. (PMO), first-generation masking functional oligomer a frame, but shortened is reading mRNA. of the mature Eteplirsen expression the disrupt some in in that a exon at result the deletions bind and exclude to to to frame (ASO) splicing DMD oligonucleotides altering antisense in pre-mRNA, of DMD use applied the the viable on of first addressing relies the location treatments skipping were novel specific interventions Exon DMD, skipping DMD. of Exon for mutations therapies emerged. of precision recently spectrum only and have pathophysiology genetics underlying the the on research of decades Despite 54,79 hl h rmr npito mrvmn nablto a o e ntepae3trial, 3 phase the in met not was ambulation in improvement of endpoint primary the While DMD ee drsigteudryn eei eetrgrls fteunderlying the of regardless defect genetic underlying the addressing gene, 77 nvivo in 76 h D oe ocrso ea oiiyse naia oestreated models animal in seen toxicity renal of concerns noted FDA The 3 DMD h rti-ua ra fAVmdae eetase nDDwas DMD in transfer gene AAV-mediated of trial in-human first The s faeoiu rlniiu vectors. lentivirus or adenovirus of use osnemttos hc opieaot1%o l M cases DMD all of 10% about comprise which mutations, nonsense 88 85–87 71–75 3,88,89 3 nadto,eiec fimngnct a oe with noted was immunogenicity of evidence addition, In 7 h D prvdeelre nSpebr21 based 2016 September in eteplirsen approved FDA The hr r he cieI irdsrpi rasin trials microdystrophin IV active three are There 83,84 hr r ubro te ml molecule small other of number a are There 80–82 tlrnhscniinlauthorization conditional has Ataluren 3 oee,det h large the to due However, 8 When 78 70 Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. .SilyJ,d ogY,Tros ,Hro W mueRsosst ia eeTher- Gene Viral to Responses Immune RW. Herzog Dystro- C, Muscular Terhorst YP, Duchenne https://doi.org/10.1016/j.ymthe.2018.07.011. Jong for de Therapy JL, Gene 2018;26(10):2337–2356. Shirley Micro-dystrophin AAV 4. Therapy. Systemic Molecular D. doi:10.1016/j.ymthe.2018.07.011 Duan MH, phy. Investiga- Brugman somatic Clinical acquired H, of with 3. Kempski Journal combined patients. M, mutagenesis SCID-X1 doi:10.1172/JCI35798 Insertional Hubank of 2019;381(5):455–464. 2008;118(9):3143–3150. al. therapy C, tion. et gene Bartholomae following D, Medicine. leukemogenesis K, Ridder causes of Schwarzwaelder De mutations Journal SJ, MR, Chatters England Mansour K, SJ, New Pike-Overzet Howe therapy. 2. Gene MG. Roncarolo KA, doi:10.1056/NEJMra1706910 High medicine. neuromuscular interventions. 1. of these era of new this costs industry, in high and forward References government, move the to groups, facing continue advocacy will are patient to field clinicians, systems how the further researchers, care on requires between This expand research health collaboration to with benefit. and fostering added along Efforts families provide ongoing, will as therapies. therapies are evaluation genetically-mediated these antibodies. (NCT03381729) AAV other of ages pre-existing with longevity replacement with older gene those and of treat safety those effectively long-term and for neuromuscular safely the SMA underlying about for the therapy learning of gene complications are the we progressing of as are care and disease multidisciplinary DMD continued in to models committed applications. animal myopathy. human remain large toward myotubular in development for X-linked successful their risdiplam and been and in like molecule has DMD conditions, systems small for neuromuscular CRISPR/Cas9 Additional other using therapy DMD. editing and replacement and these gene SMA for both and avail- development for commercially in SMA ASOs currently with and are decade SMA past therapies for the in replacement transformed gene has able disorders neuromuscular for medicine Precision Conclusions studies. preclinical unknown. in histopathology, muscle remains function of cardiac correction functional in proteins, improvement and dystrophin-associated restoring and of structural at expression models. successful the increased in been of animal results has much delivery transfer in bears gene genes AAV-mediated Utrophin function via of upregulation muscle delivery dystrophin. its for by and dystrophin, avenue substitute of can therapeutic elements double- that mutation-independent A vectors DMD. another AAV in represents via standard-of-care liver engineering therapy as size, of steroids gene sample elevations of to Surrogate hepatic modest (NCT03769116). use due underway pre-existing milder only be is or this may were trial transgene, if SMA there or placebo-controlled clear in vector blind, sample, abeparvovec not the onasemnogene is small weekday of with It each specifics this seen given ULN. or In was was times AAVrh74- as equivalent) four and weeks. than (or at years 2-4 response prednisone peaking 4-6 over of gamma-glutamyltransferase aged weaned dose with boys daily and , in mg/kg days used 1 30 was additional the vg/kg for an as 10e14 in 1:400. so elevations x to fluctuated and 2.0 up compared liver enrollment, levels of Assessment permitted transient (though Ambulatory dose were and Star age A antibodies vomiting North binding self-limited of effects. the with year adverse on period. safe, 1 common points 1-year was 2 most at treatment a least levels The over at kinase baseline. by sustained improved to creatine measures scores in using all outcome DMD reduction after and motor weeks with between), a 12 children in showed expression improvements four participants microdystrophin in functional of All microdystrophin levels and high systemic transfer revealed of promoter gene trial MHCK7 1/2a and vector phase AAVrh74 an open-label an from Results 91 iial,BGLT GLT)urglto i AAV-mediated via upregulation (GALGT2) B4GALNT2 Similarly, 37,90 98 e,a xiiga hs ramnsae lncasmust clinicians are, treatments these as exciting as Yet, l hlrnwr naweedseodrgmnpirto prior regimen steroid weekend a on were children All 8 92–94 hi lnclbnfi ncide ihDMD with children in benefit clinical Their 99,100 ti nnw ftecmiainof combination the if unknown is It 27,86,95–97 ute,gene Further, 101,102 By 90 Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. i f45Ptet n ugsin o oicto fEitn lsictos rhvso . of Archives Classifications. Existing of Modification a for Suggestions SP, and Reyna Patients KJ, 445 Swoboda of Sch sis SB, K, Neurology. Rutkove of Zerres WD, Annals atrophy. 19. muscular Arnold spinal K, infantile-onset of Krosschell history implications Natural doi:10.1002/ana.25101 JW, and al. 2017;82(6):883–891. Yankey et I BT, CS, type Darras A, atrophy Coffey Sakonju muscular SJ, spinal Kolb of Foley 18. Reghan study doi:10.1212/WNL.0000000000000741 PB, Observational 2014;83(9):810–817. Kang al. Neurology. DM, trials. et Sproule clinical WK, WB, Chung for Martens BT, ML, Darras P, Yang Kaufmann A, MP, McDermott Child RS, of Finkel Journal 17. heterogeneity. disease and classification doi:10.1177/0883073807305673 Clinical atrophy: 2007;22(8):946–951. 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Molecular doi:10.1016/j.ymthe.2020.01.001 Vectors. apy < nbr R aua itr nPoia pnlMsua toh:Ciia Analy- Clinical Atrophy: Muscular Spinal Proximal in History Natural SR. ¨ oneborn 228::AID-HUMU3 > 3.0.CO;2-9 le ,BikS ase ,Hle .Mll ffce patients affected Mildly R. Heller A, Baasner S, Blick H, uller ¨ le ,Agln .Eieilg fsia muscular spinal of Epidemiology C. Angelini E, uller ¨ 9 lae J le ,Fern´andez Bor- E, RM, Aller FJ, Alvarez ´ Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. ebrM ta.O4Sns at1 8mnhsft n xlrtr ucmso idpa (RG7916) H, risdiplam Kletzl of W, outcomes Yeung exploratory M, Tichy and M, safety Pera 18-month N, 1: Goemans part L, O.41Sunfish Servais al. J, et Kirschner M, G, Baranello Gerber E, 30];29:S184. Jun Mercuri 2020 31. 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Data may be preliminary. 9 iot ,MnyWL ct ,Pn ,DcnnkN esn ,MruiE ks H Muntoni DH, Skuse E, Mercuri relation S, in dystrophy Messina muscular N, Duchenne Deconinck in M, problems Pane behavioural M, and Scoto emotional, WPL, Neurodevelopmental, doi:10.1002/mus.20586 paradoxical the Mandy F. 2006;34(2):135–144. and in Nerve. V, types Entries and Ricotti mutation JT. Muscle 59. of Dunnen rule. overview reading-frame Den the An GJB, confirm database: Ommen that Van mutation cases IF, dystrophy Fokkema muscular dystrophinopathy JCT, Duchenne in Deutekom Leiden mutations Van A, DMD Aartsma-Rus of 2009;30(12):1657– 58. spectrum Mutation. Sampson Human Mutational MT, cohort. large Howard al. a E, et doi:10.1002/humu.21114 to techniques Gappmaier 1666. WM, diagnostic P, King modern Soltanzadeh of C, Application A, Wall patients: Niederhausern M JR, Von doi:10.1016/1 of G, Mendell DM, 1989;45(4):498–506. 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A, muscular Salmaninejad Becker 87. and Duchenne in doi:10.1097/WCO.0000000000000739 Update 2019;32(5):722–727. KM. Neurology. Flanigan MA, Waldrop 86. 15 α urgts oeua Therapy. Molecular surrogates. 2 Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363326.63434809 — This a preprint and has not been peer reviewed. Data may be preliminary. gene-therapy-in-spinal-muscular-atrophy-and-duchenne-muscular-dystrophy 1.docx currently three is Table which to medication, up enteral and daily file a age) (NCT04256265). 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