research

Since November, 2004, Charley's Fund has committed more than $14 million to medical research. Our focus is translational research – research that has a real chance of reaching human clinical trial within five years. Our varied portfolio of investments includes world-renowned universities as well as start-up biotechnology companies. We fund scientists working all over the world, from Western Australia to South Plainfield, New Jersey. Our strategy for therapeutics development has three prongs: gene therapy, drug therapy, and stem cell therapy. What follows is a complete list of projects we have funded and are actively funding.

Gene Modification Therapy

(“Exon Skipping”)

AVI Biopharma – Portland, OR
This Portland, OR-based company holds the predominant patent estate for exon skipping technology. We have funded a one-year project to conduct research and the preclinical testing of a promising morpholino compound that affects all muscles including the heart. AVI is collaborating with Dr. Steve Wilton of U of Western Australia in worldwide team effort to move this promising treatment forward.

Carolinas Medical Center -- Qilong Lu, PhD
Principal Investigator Dr. Qi Lu and his team have tested several modes of drugs useful for exon skipping. He demonstrated that these sequences worked in hums DMD cells to produce a shortened dystrophin. He continues to evaluate the systemic delivery of exon skipping drugs that can lead to functional improvement in the mouse model. He also collaborates with several research institutes and biotech companies who will use his information to design preclinical safety studies in animals prior to moving into humans. Read press release about collaboration

Prosensa - Leiden, The Netherlands
In November 2005, Charley’s Fund invested in Prosensa, a Dutch biotechnology firm that is developing a novel therapy for DMD called exon skipping. One month later, Prosensa was the first company in the world to earn orphan drug status from the FDA for this therapy. Prosensa has begun the first-in-human clinical trial of exon skipping. Read press release. In this trial, researchers are injecting the biceps of boys with DMD to test safety and efficacy. Prosensa has initiated a Phase I/II clinical trial to test intravenous systemic delivery so the therapy can be targeted to all the muscles of the body. The trail is thought to begin in lat 2008 or early 2009. For more information about this clinical trial, read an interview with Gerard Platenburg, Prosensa’s CEO.

University of Western Australia – Steve Wilton, PhD
Research pioneer Steve Wilton, PhD is developing an exon-skipping “cocktail” which will measure skipping efficiency in DMD patient cells. This research complements the work being done by AVI Biopharma, the biotechnology firm in Portland, OR that we are funding. Dr. Wilton’s work will help make exon skipping applicable to more children with DMD.

Drug Therapy

Small Molecules/Approved Drugs

AT Still University of Health Sciences -- George Carlson, PhD
Anti-Inflammatory Agents
Dr. Carlson evaluated the utility of anti-inflammatory agents that prevent muscle cell death as potential treatments for DMD. He administered two separate drugs that are currently in widespread use for other illnesses in mice with muscular dystrophy and evaluated functional improvement. Research indicates that they inhibit the NFkB pathway, an intervention that should have clinical benefit for boys with DMD. One of the drugs showed no benefit while the second dramatically inhibited NFkB and showed a moderate functional improvement. The latter compound is being considered for use in a clinical trial

BioFocus DPI – Netherlands
Utrophin Upregulation Assay
Increasing the production of the protein utrophin can compensate for the absence of dystrophin in DMD patients. The BioFocus team developed a highly sensitive assay to measure expression of utrophin in human skeletal muscle cells. The assay allowed for the screening of potentially useful drugs. Nine compounds were identified to have an increase in utrophin. Some of these drugs will now be tested in the dystrophin deficient mouse model.

Children’s National Medical Center – Kanneboyina Nagaraju, PhD
Testing Supplements and Pre-approved Drugs in a Mouse Model

Dr. Nagaraju is investigating four experimental drugs (Celastrol, Resveratrol, Thalidomide, Cyclosporine A analog) that may prevent muscle degeneration and increase muscle function. This project tests these drugs in the DMD mouse model, so we can determine whether human clinical trials are warranted. Celastrol and Debio025 were both well tolerated but did not show significant improvement in the mouse model. The other two drugs are still under investigation.

The Research Institute at Nationwide Children’s Hospital-- Paul Martin, PhD
Increase in Protein Galgt2 Helps Muscle Cells
From previous studies, Dr. Martin concluded that Galgt2, a protein that adds sugars to other proteins, could be a therapeutic target for a treatment for DMD. Mice with muscular dystrophy have a 3-fold increase in natural expression of Galgt2. This observation led Dr. Martin to conclude that Galgt2 overexpression may ameliorate the dystrophic condition. In the previous funding period, Dr. Martin developed a reporter cell line that can be used to screen compounds that would increase the expression of Galgt2. We have renewed a sponsored research agreement to conduct the drug screening with some promising results.

CombinatoRx -- Cambridge, MA
Hi-Thruput Screening
Charley's Fund has teamed with the Nash Avery Foundation and the GM Trust to invest $3.45 million in CombinatoRx, a unique pharmaceutical company focused on developing new medicines built from synergistic combinations of approved drugs. Our funding is being used for a 2-year research program with the specific aim of developing a treatment for DMD. CombinatoRx has assembled a highly qualified and motivated team for their DMD research. They are looking at millions of combinations of drugs that have been approved for other uses to see if any of the compounds can work in tandem to slow or stop the relentless progression of DMD. Dr. Benjamin Seckler and Dr. George Vella of Charley's Fund both serve on the Joint Research Committee that guides the scientific program. Click here to read a recent article about CombinatoRx in the New York Times.

University of Nevada, Reno -- Dean Burkin, PhD
Alpha-7 Integrin Upregulation
Dr. Burkin, assistant professor of pharmacology, has developed an assay (scientific test) to identify compounds that can increase the production of alpha-7 integrin, a protein that stabilizes muscle membranes. With our support, Dr. Burkin is using his assay to search two libraries of FDA-approved drugs. He has found three FDA approved drugs that show an increase in alpha-7-intergin. These compounds will be considered for testing in the dystrophin deficient mouse model. We will use his assay to screen other drug libraries to expand the search for drugs that can counteract the muscle degeneration brought on by DMD.

University of Pennsylvania – Tejvir Khurana, PhD
Utrophin Upregulation Assay
Dr. Khurana, a world renowned expert on the utrophin promoter, is testing a compound collection of FDA approved drugs using a promoter assay he developed to see if any of these compounds will increase the expression of utrophin in vitro. He is also developing a novel utrophin assay that blocks a protein which prevents utrophin expression. This assay is based on one of the awards from the DMD etank initiative

University of Washington – Stanley Froehner, PhD
Phosphodiesterase Inhibitors
Dr. Froehner is testing phosphodiesterase (PDE) inhibitors as potential drugs to treat DMD. PDE inhibitors reduce inflammation, improve blood flow in the muscle, upregulate utrophin and inhibit myostatin, a negative regulator of muscle mass. Dr. Froehner found that certain PDEs significantly improved skeletal and cardiac muscle function in the mouse model. Dr. Froehner also showed that PDEs may prevent heart damage in older mice. These PDEs are being considered for a human clinical trial.

Small Molecules/Novel Therapeutics

Project Catalyst - South Plainfield, NJ
Hi-Thruput Screening
Project Catalyst is a targeted research program designed to develop oral medications that may delay muscle degeneration in DMD. The research is being conducted by PTC Therapeutics, a New Jersey biotech firm that currently has a DMD drug in Phase II human clinical trials. This drug, called PTC 124, will benefit 10-15% of boys with DMD who have a particular genetic mutation called a “stop codon” or “nonsense mutation.” PTC is now selecting additional drug candidates that will help the remaining 85% of children with DMD by hundred of thousands of compounds. Several classes of compounds have been identified for four DMD protein targets and are being optimized for safety and efficacy. Lead candidates may eventually be tested in human clinical trials targeted for 2010.

Summit plc (formerly VASTox plc) – United Kingdom
Utrophin Upregulation
A UK-based biotechnology company, Summit plc is searching for new drugs that will increase expression of the protein utrophin. We teamed up with the Nash Avery Foundation to pay for Summit to purchase a library of 30,000 compounds so they can expand their search. Several compounds were found to increase the level of utrophin in cell culture. These compounds are being optimized for safety and efficacy. One compound from a different collection of compounds will be tested in a clinical trial some time next year.

Biologicals

Brown University -- Justin Fallon, PhD
Biglycan
Utrophin is a compensatory protein that can act as a substitute for dystrophin, the missing protein in DMD boys. Dr. Fallon has discovered that a protein called biglycan can upregulate utrophin expression in a muscular dystrophy mouse model. He has observed other beneficial effects of biglycan, including reduction of muscle fiber cell death. In Dr. Fallon’s previous studies, a single dose of biglycan was effective in the mouse model for three weeks. Dr. Fallon tested biglycan in the mouse model to show significant functional improvement. Dr. Fallon is now scaling up the production of biglycan in preparation for preclinical safety studies.

University of Minnesota - James Ervasti, PhD
TAT-Utrophin
Dr. Ervasti has come up with a way to transport utrophin -- a protein that can act as a substitute for dystrophin -- to the muscle cells. This approach requires that utrophin is attached to another protein called TAT. This new fused protein (or chimera) is then transported into the cell. Dr. Ervasti has promising preliminary results that demonstrate improvement in a mouse model treated with this therapy. Currently, Dr. Ervasti is investigating the chimera’s optimal dosage, frequency of administration, and mode of delivery. In addition, Dr. Ervasti is investigating ways to scale production of TAT-utrophin in preparation for preclinical safety and toxicology studies in animals.

STEM CELL THERAPY

University of Leuven, Belgium -- Maurilio Sampaolesi, PhD
Stem Cells
The most promising long term therapeutic strategy for DMD is correcting the genetic defect at the DNA level. Dr. Sampaolesi is developing a program for the stem cell treatment of DMD patients. He is investigating methods to culture specific stem cells called "multipotent adult progenitor cells" for potential use as therapeutic gene therapy agents. Having a supply of stem cells will permit Dr. Sampaolesi to investigate the mode of delivery that will affect as many muscle cells as possible and assess the type, number and quality of clinical grade stem cells required to obtain FDA approval to proceed with a clinical trial on DMD patients.

OTHER

DMDeTank - Worldwide
Assay Development
Charley’s Fund initiated an innovative project that taps the global scientific community to solve problems facing DMD researchers. Collaborating with InnoCentive, a web based company that matches top scientists from around the globe with relevant R&D challenges, we have compiled a “virtual” think tank of DMD and drug development experts.

The e-Tank:

identifies key problems facing DMD researchers
seeks solutions via the world wide web for financial reward
applies solutions to expedite therapeutics development

Five challenges were submitted last year and two solutions were awarded. Both the solutions are being further investigated by our collaborators.

University of Colorado -- Brian Tseng, MD, PhD
Molecular Sealant (Dr. Tseng is now at Massachusetts General Hospital)
Dr. Tseng is developing a “molecular sealant” to patch the holes in the muscles cells of boys with DMD and strengthen the membranes. The sealant, called Poloxamer 407, is approved for use in commonly used mouthwashes and drugs. It is currently undergoing human clinical trials for other diseases. Together with Charley’s Fund, this effort is being supported by the Nash Avery Foundation, the Jett Foundation and Cure Duchenne. Unfortunately this sealant did not show the desired benefits so no further work is currently planned.

UNC Animal Models Core Facility -- Randy Thresher, PhD
New Mouse Model
We have awarded a grant to the UNC animal models core facility to develop a genetically modified mouse that mimics DMD in a human. Unlike the most widely used mouse in DMD research (mdx mouse), this new animal model contains human genetic material. This new model will be used to test the efficacy of systemic exon skipping. Unfortunately this project was much more difficult than originally anticipated and although the mice incorporated the appropriate human genetic material, they were unable to reproduce to develop a colony.

On Our Radar

Acceleron Pharmaceutical
ACE-031, the lead product in Acceleron’s muscle program, is being developed to treat diseases involving the loss of muscle mass, strength and function in diseases including muscular dystrophy, amyotrophic lateral sclerosis and cancer-related muscle loss. ACE-031 works by inhibiting myostatin and other negative regulators of muscle mass thereby freeing the body to rebuild muscle tissue.

Asklepios
a biopharmaceutical company that recently launched the first human gene therapy trial targeting DMD.

Johns Hopkins University – Hal Dietz, MD.
Dr. Dietz recently found that a commonly prescribed blood pressure medication, Losartan, improved muscle regeneration and repair in the mdx mouse model.
Researchers are in the process of organizing a clinical trial for DMD cohorts.

HCT – 1026
A group in Italy recently described the use of a nitric oxide (NO)-releasing compound that also functions as an anti-inflammatory. The drug, called HCT-1026, behaves as an NO donor (stimulating the up regulation of NOS). HCT1026 was tested in mice with muscular dystrophy for one year and was shown to slow the progression of the dystrophic condition. Human clinical trials are being considered.

Santhera
a Swiss biotechnology company developing a drug (calpain blocker) that aims to slow the progression of DMD.

Dr. Giulio Cossu -- Stem Cell Therapy
Giulio Cossu and co-workers in Milan reported in the November 30th 2006 issue of Nature that dogs with muscular dystrophy who received a type of stem cell called mesangioblasts from a single donor had significant improvement over untreated control animals. Human clinical trials are being considered in the next two to three years.

Trichostatin A -- Dr. Lorenzo Puri – Burnham Institute
Trichostatin A (TSA), used to treat breast cancer patients, was found to regenerate wasted muscles in a mouse with muscular dystrophy. Plans for human trials are currently being defined.