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2012 NEWS

JANUARY

30 - (Biochemical and Biophysical Research Communications, 2012) Restoration of Muscle Fibers and Satellite Cells after Isogenic MSC Transplantation with Microdystrophin Gene Delivery

Shan-wei Feng, , Fei chen, , Jiqing Cao,  Ying-yin Liang, Xin-ming Song, Cheng Zhang  - China

 Duchenne muscular dystrophy is the most prevalent inheritable  muscle disease. Transplantation of autologous stem cells with gene direction is an ideal therapeutic approach for the disease. The current  study aimed to investigate the restoration of myofibers in mdx mice after mdx bone marrow-derived mesenchymal stem cell (mMSC)  transplantation with human microdystrophin delivery. Possible mechanisms of action were also studied. In our research, mMSCs were successfully transduced by retrovirus carrying a functional human microdystrophin gene. Transplantation of transduced mMSCs enabled persistent dystrophin restoration in the skeletal muscle of mdx mice up to the 12th week after transplantation. Simultaneous coexpression of human microdystrophin and desmin showed that implanted mMSCs are capable of long-term survival as muscle satellite cells.

25 - (Pharmacological Research, January 2012) Nitric oxide donor and non steroidal anti inflammatory drugs as a therapy for muscular dystrophies: evidence from a safety study with pilot efficacy measures in adult dystrophic patients

Maria Grazia D’Angelo, Sandra Gandossini, Filippo Martinelli Boneschi, Clara Sciorati, Sara Bonato, Erika Brighina, Giacomo Pietro Comi, Anna C. Turconi, Francesca Magri, Giuseppe Stefanoni, Silvia Brunelli, Nereo Bresolin, Dario Cattaneo, Emilio Clementi - Italy

This open-label, single centre pilot study was designed to evaluate safety and tolerability of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a non steroid anti-inflammatory drug, in a cohort of adult dystrophic patients (Duchenne, Becker and Limb-girdle muscular dystrophy). Seventy-one patients were recruited: 35, treated with the drug combination for 12 months, and 36 untreated. Safety and adverse events were assessed by reported signs and symptoms, physical examinations, blood tests, cardiac and respiratory function tests. Exploratory outcomes measure, such as the motor function measure scale, were also applied.

Good safety and tolerability profiles of the long-term co-administration of the drugs were demonstrated. Few and transient side effects (i.e. headache and low blood pressure) were reported. Additionally, exploratory outcomes measures were feasible in all the disease population studied and evidenced a trend towards amelioration that reached statistical significance in one dimension of the MFM scale. Systemic administration of ibuprofen and isosorbide dinitrate provides an adequate safety margin for clinical studies aimed at assessing efficacy.

21 - (Journal of Neuroscience Research, 2012) Motor performance of young dystrophic mdx mice treated with long-circulating prednisolone liposomes

Charlotte Weller, Jana Zschüntzsch, Gregor Makosch, Josbert M. Metselaar, Florian Klinker, Lars Klinge, David Liebetanz and Jens Schmidt - Germany

For Duchenne muscular dystrophy (DMD), a common myopathy that leads to severe disability, no causal therapy is available. Glucocorticosteroids improve patients' muscle strength, but their long-term use is limited by negative side effects. Thus, pharmacological modifications of glucocorticosteroids are required to increase the efficacy by drug targeting. Liposomal encapsulation augments systemic half-life and local tissue concentrations of glucocorticosteroids and, at the same time, reduces systemic side effects. In this study, the efficacy of novel, long-circulating, polyethylene-glycol-coated liposomes encapsulating prednisolone was compared with free prednisolone in the treatment of mdx mice, a well-established animal model for DMD. Using an objective and sensitive computerized 24-hr detection system of voluntary wheel-running in single cages, we demonstrate a significant impairment of the running performance in mdx compared with black/10 control mice aged 3–6 weeks. Treatment with liposomal or free prednisolone did not improve running performance compared with saline control or empty liposomes. Histopathological parameters, including the rate of internalized nuclei and fiber size variation, and mRNA and protein expression levels of transforming growth factor (TGF)-β and monocytes chemotactic protein (MCP)-1 also remained unchanged. Bioactivity in skeletal muscle of liposomal and free prednisolone was demonstrated by elevated mRNA expression of muscle ring finger protein 1 (MuRF1), a mediator of muscle atrophy, and its forkhead box transcription factors (Foxo1/3). Our data support the assessment of voluntary running to be a robust and reproducible outcome measure of skeletal muscle performance during the early disease course of mdx mice and suggest that liposomal encapsulation is not superior in treatment efficacy compared with conventional prednisolone. Our study helps to improve the future design of experimental treatment in animal models of neuromuscular diseases

21 - Long-term preservation of cardiac structure and function after AAV9-mediated microdystrophin gene transfer in mdx mice

 

 

 

 

 

 

 

 

 

 

 

 

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