toxin with fullerene or without fullerene. The injected muscles were

removed and stained for H&E on 1, 3, 5, 7, 14, and 28 days after the injec-

tion. Supernatants of muscle extract were prepared and western-blotting

was performed by Laemmli methods to evaluate expression of muscle pro-

teins, such as dystrophin, desmin, and nNOS. Average diameter of regener-

ate muscles 28 days after injection, cardiotoxin group and co-administered

fullerene group were 19.8 ± 7.6 lm and 27.0 ± 7.6 lm, respectively. Muscle

protein expression in co-administered fullerene group, dystrophin, desmin,

and nNOS was observed in the earlier stage by Western blot than those of

cardiotoxin group. During the experiment, no significant and critical

change was observed.We revealed that Fullerene has a function to promote

the regeneration of skeletal muscle in this experiment. We believe fullerene

and can be applied in the treatment of muscular dystrophy.

http://dx.doi:10.1016/j.nmd.2012.06.336

G.P.131

Child and family care – Supporting and empowering people living with

neuromuscular conditions

P. Martin 1, C.S. McDermott 2

1 Muscular Dystrophy Foundation, Chief Executive Office, Sydney, Austra-

lia; 2 Little Heroes Foundation, Chairman, Adelaide, Australia

A national pilot program to empower children and families adjust and

thrive after diagnosis. The unique partnership between Little Heroes

Foundation and Muscular Dystrophy Associations combined with a

mutual commitment to practical supports and quality services within local

communities is producing significant outcomes for clients and families The

Child Family Care initiative provides a range of client focused services to

assist families and clients within their local community. The service will

interface with medical and allied health services as well as offering, coun-

selling, education, well being, physical and practical supports. Interfacing

with neuromuscular clinics and hospital services, the program commenced

in South Australia and has been piloted in Queensland and New South

Wales. Opportunities to introduce services in all states and territories

are currently being explored.

http://dx.doi:10.1016/j.nmd.2012.06.337

ADVANCES IN THERAPY FOR NEUROMUSCULAR DISORDERS

– POSTER PRESENTATIONS

T.O.1

RNAi therapy for LGMD1A

J. Liu 1, L.M. Wallace 2, S.E. Garwick-Coppens 1, M.E. Hauser 3,

J.R. Mendell 4, S.Q. Harper 5

1 The Research Institute at Nationwide Children’s Hospital, Center for Gene

Therapy, Columbus, United States; 2 Ohio State University and The

Research Institute at Nationwide Children’s Hospital, MCDB Program

and Center for Gene Therapy, Columbus, United States; 3 Duke University,

Durham, United States; 4 Ohio State University and The Research Institute

at Nationwide Children’s Hospital, Pediatrics, Neurology, and Center for

Gene Therapy, Columbus, United States; 5 Ohio State University and The

Research Institute at Nationwide Children’s Hospital, Pediatrics and Center

for Gene Therapy, Columbus, United States

Limb-girdle muscular dystrophy refers to a group of 23 disorders

characterized by progressive wasting and weakness of shoulder and hip

girdle muscles. The onset and progression of LGMD varies among

individuals and genetic subtypes. Pre-clinical studies support that gene

therapy is a promising treatment approach for the LGMDs, and impor-

tantly one such strategy (for LGMD2D) was recently translated to

human clinical trials. Despite the positive direction of LGMD-targeted

gene therapies, all strategies to date focused on gene replacement

approaches for recessive forms, while treatments for dominant LGMDs

have been largely unexplored. This lack of focus on gene therapy for

dominant LGMDs arose primarily because these disorders require dis-

ease gene knockdown, and the molecular tools to feasibly accomplish this

did not exist until recently, with the emergence of RNA interference

(RNAi). We hypothesized that patients with dominantly inherited

LGMD would benefit from RNAi-mediated reduction of the pathogenic

alleles underlying their disease. In this study, we developed the first

RNAi-based, pre-clinical treatment for LGMD1A, caused by dominant

mutation in one allele of the myotilin (MYOT) gene. To do this, we engi-

neered and delivered MYOT-targeted artificial microRNA (miMYOT)

vectors to knockdown mutant MYOT in muscles of an LGMD1A mouse

model. Three months after treatment, miMYOT vectors significantly

reduced soluble mutant MYOT protein to undetectable levels, and the

protein aggregates that are characteristic of LGMD1A were either absent

or very small in treated muscles. This reduction was associated with sig-

nificantly improved muscle mass and whole muscle strength in LGMD1A

mice. We are now assessing body wide improvements of miMYOT treat-

ment following global vascular delivery. This work is an important first

step toward translating targeted RNAi gene therapy approaches for

LGMD1A, and our method could be adapted to impact a large class

of dominant muscle disorders.

http://dx.doi:10.1016/j.nmd.2012.06.338

T.O.2

Allele-specific silencing against the ALK2 mutants, R206H and G356D, in

fibrodysplasia ossificans progressiva (FOP)

H. Furuya 1, M. Takahashi 2, T. Katagiri 3, H. Hohjoh 2

1 NHO Omuta Hospital, Neuro-Muscular Center, Fukuoka,

Japan; 2 NCNP, Department of Molecular Pharmacology, Tokyo,

Japan; 3 Saitama Medical University, Research Center for Genomic Med-

icine, Saitama, Japan

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant

congenital disorder characterized by postnatal progressive heterotopic

ossification in soft tissues, especially skeletal muscle. In FOP, acute hetero-

topic ossification is induced by muscle injury, such as accidental trauma or

surgical operations. Currently, no definitive treatment exists for FOP. The

activin receptor type IA/ activin-like kinase 2 (ACVR1/ALK2) gene has

been identified as the responsible gene for both familial and sporadic cases

of FOP, and disease-associated ALK2 mutations have been found. ALK2

protein, which is one of the signaling receptors for bone morphogenetic

proteins (BMPs) and which induce heterotopic bone formation in skeletal

muscle in vivo and initiate the differentiation pathway through which myo-

blasts convert to osteoblastic cells in vitro. Chemical inhibitors such as

dorsomorphin to the pathogenic ALK2 receptors are considered possible

medical agents for FOP, but their adverse effects on normal ALK2 and

other receptors cannot be excluded. Here we describe another treatment

strategy for FOP using allele-specific RNA interference (ASP-RNAi),

and show modified small interfering RNAs (siRNAs) conferring allele-

specific silencing against disease-causing ALK2 mutants (R206H and

G356D) found in FOP, without affecting normal ALK2 allele. Thus, the

siRNAs presented here may become novel therapeutic agents for FOP,

and their induced ASP-RNAi may pave the way for the achievement of

radical treatment of FOP and/or for the relief of its severe symptoms.

Takahashi M et al. PNAS 2010;107(50):21731–6; Takahashi M et al. Gene

Therapy 2011, in press.

http://dx.doi:10.1016/j.nmd.2012.06.339

906 Abstracts / Neuromuscular Disorders 22 (2012) 804–908