|
Supported Grants:
Corporate Grant:
“Cell Transplantation Strategy For the Treatment of Amyotrophic Lateral Sclerosis”
PI: Chris Airriess, Ph.D., California Stem Cell, Inc.
$200,000(yr1)
Amyotrophic lateral sclerosis (ALS) results in motor function loss because the cells within the spinal cord that control muscles are destroyed. California Stem Cell (CSC) has developed technology to make those cells in unlimited quantity, using human embryonic stem cells (hESCs). The goal of this research is restoration of function to the muscles that control breathing in ALS patients. The greatest challenge of hESC research is to generate large amounts of one cell type in high purity for use in disease. Our company Founder was the first researcher to make large amounts of high purity cells from hESCs, which were used for treating spinal cord injuries in rats and are currently being developed for use in humans. Here, we propose to conduct safety and functional studies of this new ALS treatment. It is essential to use larger animal models to better reflect the human condition. We will also work closely with the Food and Drug Administration to ensure our studies are relevant to humans.
Corporate Grant:
“Phase II Clinical Study of rhIGF-I/rhIGFBP-3 in Myotonic Dystrophy Type 1”
PI: Geoffrey Allen, Ph.D., Insmed Incorporated
$1,043,663(yr1) $1,043,662(yr2)
Myotonic dystrophy type 1 (DM1) is characterized by muscle weakness, wasting and disruption of many body systems, including cardiac disease, decreased cognitive functioning, gastrointestinal disturbances and insulin resistance. Insmed is developing a drug, IPLEX, which has shown promise in treating disorders associated with insulin resistance and/or abnormal anabolism. To learn whether IPLEX may be beneficial to patients with DM1, we are conducting a clinical study in 60 patients with DM1. Patients will receive IPLEX or placebo for 6 months and undergo assessments to determine the effect of IPLEX on muscle strength, mass, endurance, cognitive functioning, gastrointestinal symptoms, and general health status. The results of this study will be used to plan future studies. If IPLEX is safe, well tolerated and positively affects muscle mass and strength, it offers hope of becoming the first effective treatment for muscle wasting and weakness in patients with DM1.
Corporate Grant:
“HDAC Inhibitors for Friedreich's Ataxia and Myotonic Dystrophy”
PI: James Rusche, Ph.D., Repligen Corporation
$563,513(yr1) $414,724(yr2)
Friedreich's ataxia and myotonic dystrophy are diseases with no current treatments. Recent finds of compounds that can activate critical genes provides an opportunity for new drugs. Work has begun to see if compounds can be made suitable for treating adolescent patients and deliver a safe therapy. Most often, lead compounds must be chemically modified to find a derivative potent on the target but safe enough to use in humans. A library of compounds derived from the chemical leads is being synthesized. With this library and researchers skilled in models of these diseases, we will hopefully identify a compound that is potent, safe, and active in models of FRDA and DM1. These are the objectives of the program: i) identify the optimal compound for development ii) evaluate the compounds in animal models of the human disease iii) complete pharmacology and toxicology to support human clinical testing. The conclusion will be compounds ready for clinical research in FDRA and DM1 patients.
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.
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.
Infrastructure Grant:
“International Spinal Muscular Atrophy Patient Registry”
PI: Tatiana Foroud, Ph.D., Indiana University (Indianapolis)
$33,112(yr1) $33,105(yr2) $35,129(yr3)
The International Spinal Muscular Atrophy Patient Registry was founded in 1986 to provide a link between patients and families interested in participating in research and researchers interested in studying SMA. The registry currently contains 1,568 families with 18,221 family members. The purpose of this application is to seek funds to continue the expansion and development of the International Spinal Muscular Atrophy Patient Registry and to:
- Implement new initiatives to identify, recruit and retain SMA patients and families.
- Collect more extensive and uniform clinical and epidemiological data.
- Track research study participation including enrollment, withdrawal, and completion.
- Establish international collaborations to develop and maintain a database of uniform, de-identified data in collaboration with the organization, Translational Research in Europe for the Assessment and Treatment of Neuromuscular Diseases.
- Expand awareness and use of the registry by SMA researchers.
Infrastructure Grant:
“The Development and Use of Disease-Specific Instruments for Muscular Dytrophies”
PI: Chad Heatwole, Ph.D., University of Rochester
$74,539(yr1) $67,810(yr2) $76,336(yr3)
This study is in response to a national call for clinically meaningful outcome measures in muscular dystrophy research. This project will develop, test, and validate a myotonic dystrophy disease-specific instrument of quality-of-life for use in clinical trials. The infrastructure used to create this instrument will be utilized to develop additional disease-specific instruments for both facioscapulohumeral muscular dystrophy and myotonic dystrophy type-2. The project will produce three viable research instruments, create the necessary infrastructure for further quality-of-life instrument development, and promote meaningful outcome measures in muscular dystrophy research.
Infrastructure Grant:
“Microarray based mutation detection in genes associated with inherited NMDs”
PI: Madhuri Hegde, Ph.D., Emory University
$200,000(yr1)
We propose to design a set of microarray-based tools that will enable the high-throughput comprehensive identification of genetic variants underlying inherited neuromuscular disorders (inherited NMDs) including Congenital Muscular Dystrophies (CMDs), Duchenne and Becker Muscular Dystrophy (DMD and BMD), Emery Dreifuss Muscular Dystrophy (EDMD), Limb-Girdle Muscular Dystrophies (LGMD), and Spinal Muscular Atrophy (SMA). This project will develop the technology and protocols leading to a novel highly sensitive, rapid and reliable diagnostic tool for enhanced molecular testing for inherited NMDs.
Infrastructure Grant:
“Natural History and Immunological Parameters in the GSHPMD Dog”
PI: Joe Kornegay, D.V.M., Ph.D., University of North Carolina at Chapel Hill
$284,854(yr1) $330,432(yr2) $269,578(yr3)
Before initiating gene therapy in Duchenne muscular dystrophy, the nature of the immune response to dystrophin protein or viral vector capsid antigens must be determined. Dogs with golden retriever muscular dystrophy (GRMD) express some dystrophin and should, therefore, be partially tolerized. In contrast, German shorthaired pointers with muscular dystrophy (GSHPMD) have a large deletion that encompasses the entire dystrophin gene. The complete absence of dystrophin provides a “clean” background in which to dissect the relative contributions that dystrophin and viral antigens make to the immune response. In this study, we will first systematically study the natural history of both GRMD and GSHPMD dogs from 3 months to 1 year of age using functional tests, pathology, and MRI. We will then conduct a series of experiments in both GRMD and GSHPMD dogs to determine the nature of their immune response to viral-mediated dystrophin gene therapy.
Infrastructure Grant:
“CMT North American Database”
PI: Michael Shy, M.D., Wayne State University.
$275,000(yr1)
The CMT North American Database currently includes a large number of well studied patients with different types of CMT to be available for clinical trials and clinical investigations. To improve the Database, ensure that patients are evaluated in a uniform fashion and to provide an infrastructure that will lead to high quality research for patients throughout the United States we are extending the Database and creating the North American CMT Network. Patients within the Network will be evaluated at one of six Centers of Excellence throughout the United States, DNA samples will be banked, and scoring systems for children with CMT will be established. This CMT Network will provide the infrastructure for CMT research within the United States and throughout the world.
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 Web-based 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.
COMPLETED GRANTS
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.
Status: Completed
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.
Status: Completed
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
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.
Status: Completed
Infrastructure Grant:
“MDA Bridging Funds to Support Dog Studies at UNC”
PI: Joe Kornegay, D.V.M., Ph.D., University of North Carolina at Chapel Hill. $170,000(yr1)
The increasing interest in studies using golden retrievers with muscular dystrophy (GRMD) has occurred in parallel with our move to the University of North Carolina-Chapel Hill (UNC-CH). Inherent challenges that occur with such a move have complicated our ability to meet the increasing demand for dystrophic dogs. These funds will also allow us to conduct additional pilot studies of promising therapeutic approaches and develop newly-recognized canine models.
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.
Status: Completed
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.
Status: Completed
Infrastructure
Grant:
“ALS/MDA Web-based 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.
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
|
