Navigation Links
Investigational drug tested for preventing muscle fiber death in muscular dystrophy

CINCINNATI An investigational antiviral drug currently undergoing human trials in Europe for treating Hepatitis C infections may have potential to reduce muscle cell damage in Duchenne and other forms of muscular dystrophy (MD). A research team led by Cincinnati Childrens Hospital Medical Center reported their results using three different mouse models of MD in a letter posted online March 16 by the journal Nature Medicine.

The investigational drug, Debio-025, is a known inhibitor of the protein cyclophilin D, which regulates the swelling of mitochondria in response to cellular injury. Researches decided to test the drug in mice engineered to carry MD after earlier laboratory tests showed deleting a gene that encodes cycolphilin D reduced swelling and reversed or prevented the diseases muscle-damaging characteristics. The mice were engineered as models of Duchenne muscular dystrophy and forms caused by a deficiency of two structural proteins, delta-sarcoglycan and laminin alpha2.

Similar to deleting the gene encoding cyclophilin D, we found that treatment with Debio-025 reduced mitochondrial swelling and necrotic manifestations in mice with muscular dystrophy. This is why we believe inhibiting cyclophilin D could be a new treatment strategy, said Jeff Molkentin, Ph.D., corresponding author of the study and a researcher in the Division of Molecular Cardiovascular Biology at Cincinnati Childrens. Debio-025 has already passed Phase II clinical trials in Europe and is considered safe in people, so we want to explore the possibility of conducting clinical trials in patients with Duchenne MD.

During the onset of muscular dystrophy, the loss of certain proteins critical to muscle function such as dystrophin can lead to contraction-related micro-tears in muscle fibers and an influx of calcium around muscle tissue. When this happens, cyclophilin D is instructed to make the membranes of mitochondria more permeable. This causes mitochondria to be flooded by calcium and reorganize, swell and eventually rupture. This triggers cell death in muscle fibers and leads to the progressive muscle weakness, wasting and often early death associated with muscular dystrophy.

Mice lacking the protein delta-sarcoglycan exhibited severe dystrophy and swelling in both skeletal and heart muscle. When Dr. Molkentin and his colleagues deleted the gene encoding cyclophilin D in these mice, the muscle cells returned to near normal and did not show appreciable signs of swelling and cell death. The investigators repeated the experiment with mice lacking a gene encoding laminin alpha2, which causes a more severe dystrophy, swollen skeletal muscle cells and premature death before the mice reach two months of age. In contrast, mice lacking both laminin alpha2 and cyclophilin D showed much healthier muscle cells, increased body weight and walked more. Also, 75 percent of the mice lacking laminin alpha2 and cyclophilin D lived more than three times longer than mice lacking only laminin alpha2.

These findings led the research team to look for pharmacological treatments that also could inhibit cyclophilin D. The drug cyclosporine is a well-documented inhibitor of the protein, but its use is problematic because it also inhibits a protein, calcineurin, crucial to skeletal muscle cell repair after injury and to the development of skeletal muscle cells. The advantage of Debio-025 is that while it inhibits cyclophilin D and blocks cell death in a number of situations, the drug does not suppress the immune system or block calcineurin. The drug is manufactured by DebioPharm S.A. of Lausanne, Switzerland, which provided Debio-025 for use in the study.

The researchers also found their study may have implications beyond skeletal muscle disease as cyclophilin D deletion reduced cardiac dysfunction caused by calcium-overload induced necrosis. This led the team to suggest that mitochondrial-dependent necrosis may also function as a common disease mechanism underlying a number of long-term degenerative disorders, something they plan to study in future research projects.

Muscular dystrophies are inherited disorders that mostly affect striated muscle tissue and more commonly occur in boys. This disease results in progressive muscle weakness, wasting and in many instances death. There is no known cure for muscular dystrophy, although Cincinnati Childrens is a recognized leader in disease-related research and a multi-disciplinary approach to patient treatment focused on maximizing ambulatory function and quality of life.


Contact: Nick Miller
Cincinnati Children's Hospital Medical Center

Related medicine news :

1. Enrollment completed in 2 pivotal phase III studies of the investigational cancer drug vandetanib
2. New Drug Application Submitted to FDA for Investigational Analgesic Tapentadol Immediate Release Tablets
3. UCB Announces Positive Results From Phase II Clinical Trial of Investigational Anti-Epilepsy Drug Brivaracetam
4. SGX Pharmaceuticals Submits Investigational New Drug Application for SGX523, a Highly Potent, Selective, Orally Bioavailable cMET Inhibitor
5. MetaCure(TM) Launches Investigational Study of Gastric Stimulator for Patients With Type 2 Diabetes Who are Overweight
6. Abbotts Investigational SIMCOR(R) Offers Comparable LDL Lowering to Simvastatin and Significantly Raises HDL and Lowers Triglycerides in Phase III Study
7. Dynavax and Merck & Co., Inc. Announce Partnership to Develop HEPLISAV(TM), an Investigational Hepatitis B Vaccine Currently in Phase 3
8. Ono and Medarex Announce Allowance of Investigational New Drug Application for Fully Human Anti-PD1 Antibody
9. Supratek Pharma Inc. announced today that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for SP1049C for the treatment of metastatic adenocarcinoma of the upper gastrointestinal tract
10. Accentia announces investigational new drug application for Revimmune for refractory MS
11. FDA Accepts New Drug Application for Priority Review of Investigational HIV Treatment TMC125
Post Your Comments:
(Date:10/13/2015)... ... October 13, 2015 , ... ActivePDF, a ... PDF automation tool to batch conversions of CAD drawings, plans, and diagrams ... fidelity. , CADConverter eliminates the complexity requirement of specialized applications to view CAD ...
(Date:10/13/2015)... ... October 13, 2015 , ... ... the world’s first commercially-available next-generation sequencing laboratory test for bacterial vaginosis- a ... and Obstetrics in Vancouver, BC, Canada. , In a presentation entitled: ...
(Date:10/12/2015)... ... October 13, 2015 , ... ... biannual Heroes in Recovery Awards at Foundations Recovery Network’s Moments of Change conference ... the one-of-a-kind awards to Noah Levine and Dean Dauphinais who exemplify the ideals ...
(Date:10/12/2015)... CA (PRWEB) , ... October 12, 2015 , ... According to an article ... data from adults today versus those of a similar group taken in 1988 has shown ... that a person in 2008 with the same diet as someone in 1971 would be ...
(Date:10/12/2015)... ... October 12, 2015 , ... Amerec , a leader in ... and skin care equipment, will be displaying custom sauna and steam room solutions at ... high-end resorts and spas as customers, SpaEquip is recognized for their ability to assist ...
Breaking Medicine News(10 mins):
(Date:10/12/2015)... Oct. 12, 2015  CME Group,s Center for Innovation ... CEO of Theranos, is the 11 th recipient of ... the revolutionary blood diagnostics company, Theranos , to change ... in a new era of preventive care. CME Group will ... Leadership Conference in Naples, Florida , ...
(Date:10/12/2015)... , October 12, 2015 ... - Pipeline Review, H2 2015 market research report ... R&D pipelines by identifying new targets and MOAs ... . --> ... pipeline spread across 62 pages, analyzing 6 companies, ...
(Date:10/12/2015)... VALLEY COTTAGE, New York , October 12, 2015 /PRNewswire/ ... Market Insights (FMI) delivers key insights on the global vital ... Signs Monitoring Devices Market: Global Industry Analysis and Opportunity Assessment ... to expand at a healthy CAGR of 9.5% and 9.2% ... period, due to factors, regarding which FMI offers major insights ...
Breaking Medicine Technology: