prostaglandin-d2 and Muscular-Dystrophy--Duchenne

Duchenne muscular dystrophy (DMD) is the most common form of inherited muscle disease and is characterized by progressive muscle wasting, ultimately resulting in the death of patients in their twenties or thirties. DMD is characterized by a deficiency of the muscle dystrophin as a result of mutations in the dystrophin gene. Currently, no effective treatment for DMD is available. Promising molecular therapies which are mutation-specific have been developed. Transformation of an out-of-frame mRNA into an in-frame dystrophin message by inducing exon skipping is considered one of the approaches most likely to lead to success. We demonstrated that the intravenous administration of the antisense oligonucleotide against the splicing enhancer sequence results in exon skipping and production of the dystrophin protein in DMD case for the first time. After extensive studies, anti-sense oligonucleotides comprising different monomers have undergone clinical trials and provided favorable results, enabling improvements in ambulation of DMD patients. Induction of the read-through of nonsense mutations is expected to produce dystrophin in DMD patients with nonsense mutations, which are detected in 19% of DMD cases. The clinical effectiveness of gentamicin and PTC124 has been reported. We have demonstrated that arbekacin-mediated read-through can markedly ameliorate muscular dystrophy in vitro. We have already begun a clinical trial of nonsense mutation read-through therapy using arbekacin. Some of these drug candidates are planned to undergo submission for approval to regulatory agencies in the US and EU. We hope that these molecular therapies will contribute towards DMD treatment.

Topics: Animals; Codon, Nonsense; Dibekacin; Dystrophin; Exons; Gentamicins; Humans; Mice; Molecular Targeted Therapy; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense; Pathology, Molecular; Prostaglandin D2

Topics: Animals; Codon, Nonsense; Dystrophin; Exons; Frameshift Mutation; Genetic Therapy; Humans; Molecular Targeted Therapy; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense; Prostaglandin D2

Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disease, characterized by progressive skeletal muscle atrophy and weakness. DMD is caused by mutations in the dystrophin gene, which encodes for the cytoskeletal protein dystrophin. DMD is one of the most common types of muscular dystrophies, affecting approximately 1 in 3,500 boys. There is no complete cure for this disease. Clinical trials for gene transfer therapy as a treatment for DMD have been performed but mainly in animal models. Hematopoietic prostaglandin (PG) D synthase (H-PGDS) was found to be induced in grouped necrotic muscle fibers of DMD patients and animal models, mdx mice, and DMD dogs. We found an orally active H-PGDS inhibitor (HQL-79) and determined the 3D structure of the inhibitor-human H-PGDS complex by X-ray crystallography. Oral administration of HQL-79 markedly suppressed prostaglandin D

Topics: Administration, Oral; Animals; Crystallography, X-Ray; Depression, Chemical; Disease Models, Animal; Disease Progression; Dogs; Drug Design; Enzyme Inhibitors; Humans; Intramolecular Oxidoreductases; Lipocalins; Male; Mice; Molecular Targeted Therapy; Muscles; Muscular Dystrophy, Duchenne; Piperidines; Prostaglandin D2

Patients with Duchenne muscular dystrophy (DMD) exhibit increased prostaglandin D. We investigated the involvement of PGD. Sixty-one male children with DMD and thirty-five age-matched controls were enrolled in the study. DMD patients were divided into "ambulant" and "non-ambulant" groups, which were further subdivided into "steroid" and "non-steroid" therapy groups. Levels of the PGD. DMD patients had significantly higher levels of creatinine-corrected t-PGDM in spot urine samples as compared with the control group. Additionally, both ambulant and non-ambulant DMD groups had significantly higher levels of t-PGDM as compared with controls, with no significant difference in t-PGDM levels observed between steroid and non-steroid groups. Moreover, total creatinine excretion in 24-hour urine samples was significantly lower in DMD patients as compared with controls, and although DMD patients had lower muscle mass than controls, their overall levels of t-PGDM did not differ significantly from those in the non-ambulant and control groups.. PGD

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Creatinine; Disease Progression; Humans; Male; Muscular Dystrophy, Duchenne; Prostaglandin D2

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by muscle dystrophin deficiency. Downstream of the primary dystrophin deficiency is not well elucidated. Here, the hypothesis that prostaglandin D2 (PGD2)-mediated inflammation is involved in the pathology of DMD was examined by measuring tetranor PGDM, a major PGD2 metabolite, in urine of DMD patients.. We measured tetranor PGDM in urine using LC-MS/MS. First morning urine samples were collected from genetically confirmed DMD patients and age-matched healthy controls aged 4 to 15y.. The urinary tetranor PGDM concentration was 3.08±0.15 and 6.90±0.35ng/mg creatinine (mean±SE) in 79 control and 191 DMD samples, respectively. The mean concentration was approximately 2.2-times higher in DMD patients than in controls (p<0.05). Remarkably, urinary tetranor PGDM concentrations in DMD patients showed chronological changes: it stayed nearly 1.5 times higher than in controls until 7y but surged at the age of 8y to a significantly higher concentration.. Urinary tetranor PGDM concentrations were shown to be increased in DMD patients and became higher with advancing age. It was indicated that PGD2-mediated inflammation plays a role in the pathology of DMD.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Chromatography, Liquid; Humans; Muscular Dystrophy, Duchenne; Prostaglandin D2; Tandem Mass Spectrometry