Supported Grants:

Corporate Grant:
“The Identification and Validation of Therapeutic Targets for ALS Clinical Development”
PI: Steve Perrin, Ph.D., ALS Therapy Development Institute
$6,000,000(yr1) $6,000,000(yr2) $6,000,000(yr3)

The Muscular Dystrophy Association (MDA) and ALS Therapy Development Institute (ALS-TDI) are collaborating on a program to comprehensively characterize disease progression in ALS using animal models of neurodegeneration and ALS clinical samples. The unbiased approaches of genomics, proteomics, and genetics will assist in understanding biological mechanism associated with disease susceptibility, onset, and progression. An unparalleled secondary validation process will be implemented using in vivo and in vitro technologies to prioritize the most relevant molecules associated with disease biology. Proof of concept studies will be evaluated in murine models of neurodegenerative disease to assess the effects of putative therapeutics on surrogate markers of disease as well as survival. From these studies the ALS-TDI will develop validated therapeutic targets ready for pre clinical and clinical development and deliver diagnostic and prognostic disease biomarkers for use in clinical applications.

Corporate Grant:
“Phase Ib/II Study of Mini-Dystrophin Gene in AAV Vector”
PI: R. Jude Samulski, Ph.D., Asklepios Biopharmaceutical Inc.
$1,162,371 (yr1) $1,015,171 (yr2) $225,828 (yr3)

Supported by a 2004 TR-CG grant from MDA, AskBio is finishing a Phase Ia gene therapy clinical trial for Duchenne muscular dystrophy (DMD) to asses the safety of a novel chimeric adeno-associated virus carrying a minidystrophin gene injected directly into the muscles of subjects with DMD. The 2006 project will build upon the preclinical and safety data generated from the Phase Ia study to evaluate safety and optimize a blood vessel-mediated regional limb delivery technique using large animal models. The data developed in these animal models will be submitted to the appropriate regulatory bodies for initiation of a Phase Ib clinical study in DMD subjects.

Augie’s Quest Grant:

“Resequencing the Variable Human Genome in Sporadic ALS”
PI: Dietrich Stephan, Ph.D., Translational Genomics Research Institute.
$652,056(yr1)

The ability to predict who will develop ALS prior to disease onset is crucial to life planning and to the success of early interventions. Additionally, new therapeutics with better efficacy and lower toxicity can be developed based on a firm understanding of the genes/proteins which, when misbehaving, predispose to this tragic disorder. The work at TGen described in this proposal may lead to 1) a diagnostic test for sporadic ALS, and 2) an understanding of the biological underpinnings of sporadic ALS so we can work toward intelligent therapies.

IND-Planning Grant:
“Toxicology and Phase I Studies of Antisense ISIS 333611 in Familial ALS”
PI: Timothy Miller, M.D., Ph.D., University of California, San Diego
$718,384(yr1) $312,739(yr2)

Some familial cases of ALS are caused by mutations in superoxide dismutase 1 (SOD1).  Mutated SOD1 is toxic to the nerves that innervate muscles.  Decreasing mutant SOD1 is likely to benefit patients with SOD1 mutations.  ISIS 333611, an antisense oligonueotides causes degradation of SOD1 RNA and thus protein.  We plan to infuse ISIS 333611 into the fluid that surrounds the brain and spinal cord.  We are seeking funding for safety testing of this compound first in animals, and then in SOD1 ALS patients.

IND - Planning Grant:
“Transfer of Alpha-Sarcoglycan Gene to LGMD2D Patients”
PI: Jerry Mendell, M.D., Columbus Children’s Research Institute.
$60,000(yr1) $60,000(yr2) $60,000(yr3)

This project is a form of gene therapy for limb girdle muscular dystrophy (LGMD2D). The disease is caused by an abnormal alpha-sarcoglycan gene. The disease causes severe weakness of the arms and legs and may lead to loss of ambulation. In the proposed study, a leg muscle of LGMD2D patients will receive the normal alpha-sarcoglycan gene to replace the defective one. A successful study will lay the groundwork for replacement of the gene to many muscles of the body in this and other forms of muscular dystrophy.

Infrastructure Grant
“Clinical Research Network for Friedreich’s Ataxia”
PI: David Lynch, M.D., Ph.D., Children’s Hospital of Philadelphia
$285,801(yr1) $200,914(yr2) $140,877(yr3)
Using recent support from the MDA and FARA, a group of investigators collaborated on development of clinical measures that can quantitatively assess FA.  While a large amount of measure refinement remains to be performed, the data from their collaboration provide a framework for further investigation and for creating a network for performing further clinical translational research including clinical trials.

Infrastructure Grant:
“ALS/MDA C.A.R.E. Database”
PI: Robert G. Miller, M.D., California Pacific Medical Center
$140,135 (yr1) $140,120(yr2) $144,750(yr3)
The ongoing ALS CARE program is a voluntary multicenter registry that has provided a unique source of information that may be used to improve the care of patients with ALS. The major focus of the new Web-based initiative will be to obtain long-term follow-up data and information about quality of life as well as survival. These data will be used to evaluate variations in patient care, adherence to standards of care and published practice parameters and also to help design clinical trials and epidemiological studies in ALS. An additional important focus of the Web-based ALS database will be to educate participating patients and visitors to the home page about ongoing clinical trials and clinical research studies, as well as to present an ongoing example of the role of the MDA/ALS division in the care of ALS patients nationwide.

Infrastructure Grant:
“A Monoclonal Antibody Resource for Genetic Neuromuscular Disease”
PI: Glenn Morris, Ph.D., North East Wales Institute
$134,854(yr1) $114,034(yr2) $117,176(yr3)

Professor Morris's Biochemistry Group has, over the past 20 years, built up a library of monoclonal antibodies for neuromuscular disease research, diagnosis and clinical trials. A collection of over 150 "exon-specific" antibodies against dystrophin is, and will continue to be, especially useful internationally in trials of potential therapies for Duchenne muscular dystrophy. Very popular antibodies have also been produced for research, diagnosis and drug evaluation in spinal muscular atrophy, Emery-Dreifuss muscular dystrophy, laminopathies and myotonic dystrophy. This project will ensure that these antibodies will continue to be available to researchers for the foreseeable future and will also add to and refine the library.

Infrastructure Grant:
“CMT North American Database”
PI: Michael Shy, M.D., Wayne State University.
$133,474(yr1) $116,880(yr2) $211,641(yr3)

The CMT North American Database is created to provide a large number of well studied patients with different types of CMT to be available for clinical trials and to answer questions such as whether certain medications exacerbate CMT, whether pregnancy exacerbates CMT or whether exercise helps CMT. In addition the Database will allow investigators to determine which mutations cause severe forms of CMT and to identify groups of patients who may be afflicted with novel forms of CMT. Patient confidentiality is strictly maintained in the Database.

Infrastructure Grant:
“Clinical Manufacturing of AAVI vector in support of a Phase I/II gene transfer study in limb girdle muscular dystrophy Type 2D.”
PI: Richard Mulligan, Ph.D., Harvard Medical School.
$300,000(yr1)

The overall goal of this project is to develop and effective form of gene therapy for limb girdle muscular dystrophy Type 2D (LGMD2D). Specifically, the clinical study will attempt to correct the underlying defect in muscular dystrophy caused be alpha sarcoglycan (SG) deficiency. In such a disorder, there is severe weakness of the arms and legs that often leads to loss of ambulation. In the proposed study, a leg muscle of LGMD2D patients will receive the normal, replacement gene (alpha-SG) to a lower leg muscle. A successful study will lay the groundwork for replacement of the gene in many muscles of the body. The manufacturing of vector encoding a normal, functional alpha-SG gene represents a critical step in the path to clinical trials for patients with LGMD2D.

COMPLETED GRANTS

Corporate Grant:
“Phase I/II Study of Mini-Dystrophin Gene in AAV Vector”
PI: R. Jude Samulski, Ph.D., Asklepios, Biopharmaceutical Inc.
$932,911 (yr1) $640,261(yr2)

The goal of this proposal is to carry out a double-blinded dose escalation Phase I/II gene therapy safety trial for Duchenne muscular dystrophy (DMD). A novel recombinant adeno-associated virus (AAV) vector carrying a functional mini-dystrophin gene will be utilized in these studies. Safety is the primary outcome measure of this trial. In addition to safety measurements, the protocol has been designed to obtain efficacy data. The long-term objective is to design, test develop and market a gene therapy approach for the treatment of DMD.
Status: Completed; Results expected Summer of 2007

Corporate Grant:
“PTC 124 Treatment for Duchenne Muscular Dystrophy”
PI: Langdon Miller, M.D., PTC Therapeutics
$1,023,460 (yr1) $476,540(yr2)

Some patients have Duchenne muscular dystrophy (DMD) due to a nonsense mutation, or a premature stop codon, in their dystrophin gene. The presence of the nonsense mutation instructs the cellular protein production machinery to prematurely stop making dystrophin, resulting in a shortened, functionless dystrophin molecule that cannot maintain muscle structure and strength. PTC 124 is a new drug that may allow the cellular protein production machinery to ignore this abnormal stop signal, thereby restoring the production of full-length functional dystrophin. The ultimate aim of the proposed development program described in this grant application is to gain regulatory approval of PTC 124 as a treatment of patients with DMD resulting from a nonsense mutation in the dystrophin gene.
Status: Completed; http://www.mda.org/research/061021dmd_trial_prem_results.html

Infrastructure Grant:
“ALS/MDA C.A.R.E. Database”
PI: Robert G. Miller, M.D., California Pacific Medical Center
$146,959(yr1) $158,514(yr2) $160,848(yr3)

The ongoing ALS CARE program is a voluntary multi-center registry that has provided a unique resource to provide information that may be used to improve the care of patients with ALS. The major focus of the new Web-based initiative will be to obtain long-term follow up data and information about quality of life as well as survival. These data will be used to evaluate variations in patient care, adherence to standards of care and published practice parameters and also to help design clinical trials and epidemiological studies in ALS. An additional important focus of the Web-based ALS database will be to educate participating patients and visitors to the home page about ongoing clinical trials and clinical research studies, as well as to present an ongoing example of the role of the MDA/ALS division in the care of ALS patients nationwide.
Status: Completed;
http://www.als-mda.org/research/news/061013als_registries.html

Infrastructure Grant:
“A monoclonal Antibody Resource for Genetic Neuromuscular Disease”
PI: Glenn Morris, Ph.D., North East Wales Institute
$117,437 (yr1) $99,429 (yr2) $104,579 (yr3)

Professor Morris’s biochemistry group has, over the past 20 years, built up a library of monoclonal antibodies for neuromuscular disease research, diagnosis and clinical trials. A collection of over 150 “exon-specific” antibodies against dystrophin is, and will continue to be, especially useful internationally in trials of potential therapies for Duchenne muscular dystrophy. Very popular antibodies have also been produced for research, diagnosis and drug evaluation in spinal muscular atrophy, Emery-Dreifuss muscular dystrophy and myotonic dystrophy. This project will ensure that these antibodies will continue to be available to researchers for the forseeable future and will also add to and refine the library.
www.rjah.nhs.uk/cind/morrisge/mabs.htm
Status: Completed; Results

Wellstone Cooperative Centers for Muscular Dystrophy Research:
In 2003 MDA developed an agreement with the National Institutes of Health (NIH) to collaborate in providing supplemental funding to three cooperative research centers for muscular dystrophy research (later named “Wellstone” centers in honor of the late Senator Paul D. Wellstone). NIH offered up to $1 million per year for five years for each of the centers and MDA supplemented this amount with an award of up to $500,000 per year for three years for each center. See http://www.mda.org/news/030521partner.html for more information about this initiative.

Successful NIH center grantees were asked to focus their MDA supplemental support on the translational aspects of their planned research project. The following centers are supported through this effort:
Status: Completed

“MDA Cooperative Center Supplement: Seattle, WA”
PI: Jeffrey Chamberlain, Ph.D., University of Washington
$499,968 (yr1) $499,968(yr2) $499,968(yr3)

MDA supplemental funding supports 4 scientific projects and 4 cores:

Project 1: Preclinical studies and development of phase I clinical trial for gene transfer in DMD
Project 2: Test of AAV vectors in K9 DMD model
Project 3: Optimizing muscle-specific regulatory gene cassettes for human muscle gene therapy
Project 4: Molecular pathogenesis of myotonic dystrophy
Core A: Administrative Core
Core B: Viral Vector Core
Core C: Diagnostic and Genetic Counseling Core
Core D: Immunology Core
Extension Pending

“MD Cooperative Center Supplement: Pittsburgh”
PI: Joseph Glorioso, Ph.D., University of Pittsburgh
$500,000(yr1) $500,000(yr2) $500,000(yr3)

MDA supplemental funding supports 4 scientific projects and 3 cores:

Project 1: Developing clinical outcomes for gene transfer
Project 2: Preclinical gene therapy in a large animal model of DMD
Project 3: Muscle stem cell-based therapies for cardiomyopathy and skeletal muscle degeneration
Project 4: Functional genomics studies of early myogenic differentiation
Core A: Administrative Core
Core B: AAV Vector Core
Core C: Large animal Core
Status: Completed

“MD Cooperative Center Supplement: Rochester”
PI: Richard Moxley, M.D., University of Rochester
$499,000(yr1) $499,000(yr2) $500,000(yr3)

MDA supplemental funding supports 3 scientific projects and 3 cores:

Project 1: Mouse muscle-bind model of myotonic dystrophy
Project 2: Effects of somatokine on myotonic dystrophy type 1
Project 3: Position effect and vascular adaptation in FSHD
Core A: Administrative Core
Core B: Repository Core
Core C: Imaging Core
Status: Completed