Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles

Qi Long Lu, Adam Rabinowitz, Yun Chao Chen , Toshifumi Yokota, HaiFang Yin, Julia Alter, Atif Jadoon , George Bou-Gharios, and Terence Partridge - United Kingdom

Antisense oligonucleotide-mediated alternative splicing has great potential for treatment of Duchenne muscular dystrophy (DMD) caused by mutations within nonessential regions of the dystrophin gene. We have recently shown in the dystrophic mdx mouse that exon 23, bearing a nonsense mutation, can be skipped after intramuscular injection of a specific 2'-O-methyl phosphorothioate antisense oligoribonucleotide (2OMeAO). This skipping created a shortened, but in-frame, transcript that is translated to produce near-normal levels of dystrophin expression. This expression, in turn, led to improved muscle function. However, because DMD affects muscles body-wide, effective treatment requires dystrophin induction ideally in all muscles. Here, we show that systemic delivery of specific 2OMeAOs, together with the triblock copolymer F127, induced dystrophin expression in all skeletal muscles but not in cardiac muscle of the mdx dystrophic mice. The highest dystrophin expression was detected in diaphragm, gastrocnemius, and intercostal muscles. Large numbers of fibers with near-normal level of dystrophin were observed in focal areas. Three injections of 2OMeAOs at weekly intervals enhanced the levels of dystrophin. Dystrophin mRNA lacking the targeted exon 23 remained detectable 2 weeks after injection. No evidence of tissue damage was detected after 2OMeAO and F127 treatment either by serum analysis or histological examination of liver, kidney, lung, and muscles. The simplicity and safety of the antisense protocol provide a realistic prospect for treatment of the majority of DMD mutations. We conclude that a significant therapeutic effect may be achieved by further optimization in dose and regime of administration of antisense oligonucleotide.

 

Should Foot Surgery Be Performed for Children With Duchenne Muscular Dystrophy?

J. Pediatr. 2005;25:95-7

Khristinn Kellie Leitch,, Naweed Raza, Doug Biggar,  Derek Stephen, James G. Wright   and Benjamin Alman -  Canada

Abstract:

The authors conducted a retrospective study to determine the outcome of foot surgery in full-time wheelchair users with Duchenne muscular dystrophy. Medical records on all 88 teenaged boys with Duchenne muscular dystrophy treated at the authors’ institution were obtained and reviewed. Patients completed questions about shoe wear, pain, hypersensitivity, and cosmesis, and a foot examination was performed. There were no significant differences between patients who did and did not receive foot surgery with respect to shoe wear (p> . 0.05), pain (p> . 0.05), hypersensitivity (p> . 0.05), or cosmesis (p> . 0.05). Hindfoot motion was significantly better (p> . 0.05) but equinus contracture was significantly worse (p> . 0.05) in patients who had not had surgery.

 

 

 

Coagulation system activated in Duchenne muscular dystrophy patients with cardiac dysfunction

Brain & Development, 2004

Toshio Saito, Yuko Yamamoto, Tsuyoshi Matsumura, Sonoko Nozaki,Harutoshi Fujimura, Susumu Shinno - Japan

Abstract

We investigated basic abnormalities of coagulation and fibrinolysis in Duchenne muscular dystrophy (DMD) patients with cardiac dysfunction. Forty seven patients with DMD, aged 13–37 years old, were enrolled. Based on left ventricular ejection fraction (LVEF) results determined by echocardiography, patients were divided into 3 groups: LVEF less than 30% (markedly depressed group), LVEF between 30 and 50% (slightly depressed), and LVEF greater than 50% (normal). We measured serum levels of total fibrin and fibrinogen degradation products (FDP), as well as plasma fibrinogen, thrombin–antithrombin complex (TAT), prothrombin fragment (F1C2), and D-dimer. The levels of TAT and F1C2 in the markedly depressed group were significantly elevated compared with the other groups, whereas FDP, fibrinogen, and D-dimer levels did not differ among the groups. We concluded that activated coagulation is associated with cardiac dysfunction in patients with DMD.