Cure CMD funds $280,000 in research in 2010, bringing totals spent on CMD research in the last two years to over $1/2 million. Two years funding in partnership with SAM. Per Cure CMD’s Chairman, Anne Rutkowski, “Funding at this level has brought an increased focus to CMD science and drives the identification of new treatment strategies. We would like to express our thanks to the expanding CMD community who make these grants possible and the Cure CMD SMAB who provide expert guidance and review”.
2010 Cure CMD Translational Grant Awards
Olga Igoucheva, PhD, Jefferson University ($50,000/yr x 2 years)
Stem Cell therapy for collagen VI congenital muscular dystrophy
Collagen VI-related muscle disorders have recently emerged as one of the most common types of congenital muscular dystrophies (CMD). Bethlem myopathy and Ullrich congenital muscular dystrophy represent the mild and severe end of a clinical continuum associated with dysfunction of collagen type VI, a connective tissue protein present in almost all tissues. Patients manifest muscle weakness and connective tissue abnormalities, including joint contractures and distal hyperlaxity. Severely affected patients are wheelchair-bound and suffer from early respiratory failure. Currently, there is no specific treatment for this disabling and life-threatening disease.
Stem cells isolated from adult human tissues are able to expand in number and reprogram to become muscle cells and various connective tissue cell types in a laboratory setting. These cells lack significant immunogenicity, and their safety as donor cells for transplantation without immunosuppressive drugs has been demonstrated in a large number of clinical trials. Moreover, recent studies have indicated that the adult stem cell treatment results in decreased inflammation, fibrosis and cell death, mediated by growth factors secreted from them.
Our preliminary studies have shown that the adult stem cells produce and secrete collagen VI.Together, these findings suggest that adult stem cell therapy will be an effective treatment strategy for collagen VI CMD. In this application, we propose to test the hypothesis that adult stem cells can serve as donor cells for therapy in a mouse model of collagen VI CMD. Adult stem cells isolated from mouse and human tissues will be delivered to mice deficient in collagen VI by intramuscular and systemic injections. The efficacy of the cellular therapy will be evaluated at different time points after cell transplantation. The experiments proposed will serve as pre-clinical studies, providing the basis for future clinical testing in collagen VI CMD patients.
Sweta Girgenrath, PhD, Boston University ($50,000)
To evaluate the efficacy of RAP-031 Treatment of Dystrophic, Inflammatory and Regenerative Deficiencies in Merosin Deficient Congenital Muscular Dystrophy Animal Model (dyw)
Merosin Deficient CMD (MDC1A) is one of the two most common forms of congenital muscular dystrophy that is characterized by extensive muscle wasting. RAP-031 is a compound, produced by Acceleron that is known to increase muscle mass. It is being developed for the treatment of patients with neuromuscular diseases to restore muscle mass and function. We propose to test the efficacy of a therapeutic protein compound, RAP-031 in the mouse model for MDC1A. We will specifically test if this compound results in increasing life span and improve muscle growth.
Valerie Allamand, PhD, Institute of Myology, France ($50,000/year x 2 years)
PTC suppression in a novel model of ColVI-myopathies
Collagen VI-myopathies are caused by a deficiency of collagen type VI (ColVI), a protein that contributes to the architectural structure of muscle and also to its maintenance and survival. ColVI myopathies constitute a large spectrum of clinical presentations ranging from severe,early-onset phenotypes, to intermediate and later-onset, milder phenotypes. The extremities of this spectrum were previously described as Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy.
Tremendous progress has been achieved in the last decade to provide accurate molecular diagnosis to the patients and their families, and to understand the mechanisms leading to these disorders. Based on our experience in the diagnosis of ColVI-myopathies, we have chosen to focus our efforts on therapies aiming to restore the expression of the deficient ColVI molecule.
We have developed a novel mouse model carrying a mutation in the Col6a2 gene, based on the mutation identified in a patient with a severe phenotype. The mutation introduced leads to a premature termination codon (PTC) which triggers the specific degradation of the Col6a2 transcript and the absence of ColVI in the skeletal muscle from these animals,leading to a myopathic phenotype. The overall objective of this project is to evaluate the therapeutic potential of 2 pharmacological approaches in this animal model: 1) inhibiting transcript degradation, induced by a specific cellular surveillance machinery, and 2)forcing the translation of the PTC introduced in the Col6a2 gene. These experiments will provide pre-clinical data regarding the efficiency of pharmacological therapies for ColVI myopathies due to nonsense mutations, estimated to about 11% of mutations identified so far.
Susan Brown, PhD, Royal Veterinary College, UK ($30,000/ year x 2 years)
Validation of an animal model for therapeutic testing in the dystroglycanopathies
Many muscular dystrophies are due to a defect in proteins that link the inside of the muscle fibre with the extracellular matrix. The ‘dystroglycanopathies’ are secondary to a problem in the way alpha-dystroglycan is decorated with sugars. These sugars determine how alpha-dystroglycan interacts with proteins in the extracellular space and in doing so contribute to the integrity of the basement membranes of muscle and in some patients, the eye and brain as well.
We have recently generated a mouse with a selective deficiency of Fukutin Related Protein (FKRP) in muscle. This mouse shows a reduction in muscle alpha dystroglycan glycosylation as do patients with FKRP mutations. If we are to develop effective forms of therapy for this group of disorders we now need to define the disease process in this mouse so that we have clearly defined parameters on which to judge whether a treatment is likely to be effective or not. In the present proposal we aim to evaluate disease progression in this mouse and use it to determine if the up-regulation of LARGE is effective in preventing or arresting the characteristic pattern of muscle fibre degeneration and improving mouse function.
2009 Cure CMD Translational Grant Awards: Year Two
Denis Guttridge, Ohio State University Medical Center, $50,000 Year Two
Goal: Study the role of NFKB signaling in Merosin Deficient CMD and treatment with Nemo Binding Peptide
Sweta Girgenrath, Boston University, $50,000 Year Two
Goal: Study the role of combinatorial therapy to target Merosin Deficient CMD