research

Since November, 2004, Charley's Fund has committed more than $15 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. Our strategy for therapeutics development has three prongs: gene therapy, drug therapy, and stem cell therapy. Below please find a complete list of projects we have funded and are actively funding.

Gene Modification Therapy

(“Exon Skipping”)

AVI Biopharma – Bothell, WA
This Portland, OR-based company holds the predominant patent estate for exon skipping technology. We have funded research and the preclinical testing of promising morpholino compounds that affect all muscles including the heart. We have agreed to extend our funding to AVI with an additional $3 million. The promising drug candidate will soon be in the final stages of preclinical evaluation, including efficacy and safety and toxicity studies. AVI has collaborated with Dr. Steve Wilton of U of Western Australia in worldwide team effort to move this promising treatment forward. Please click here to read the press release about the extended collaboration.

Carolinas Medical Center -- Qilong Lu, PhD – Charlotte, NC
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 human DMD cells to produce a shortened dystrophin. He evaluated 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. Please click here to read an abstract of the results.

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. 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 trial began at the end of 2008. For more information about exon skipping, please read the following report.

University of Western Australia –Steve Wilton, PhD - Nedlands, Australia
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 – Kirksville, Missouri
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. Please click here to read about the results of the study.

BioFocus DPI – Leiden, the 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 as having the potential to increase the production of utrophin. Some of these drugs will now be tested in the dystrophin deficient mouse model. Charley’s Fund has extended its collaboration to screen a larger library. For more information, please click here.

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

Dr. Nagaraju investigated four experimental drugs (Celastrol, Resveratrol, Thalidomide, Cyclosporine A analog) that may prevent muscle degeneration and increase muscle function. This project tested these drugs in the DMD mouse model to determine whether human clinical trials were warranted. All of the drugs were well tolerated but did not show significant improvement in the mouse model. Charley’s Fund has extended their collaboration with Dr. Nagaraju to include some of the drugs identified in our screening initiative. These drugs will now be tested in the DMD mouse model.

The Research Institute at Nationwide Children’s Hospital-- Paul Martin, PhD -- Columbus, Ohio
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 over expression 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 drug screening and some compounds will be tested in the DMD mouse model.

CombinatoRx --Cambridge, MA
High-Throughput Screening of Combinations of Approved Drugs
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. Promising combinations of drugs have been found for two targets and plans are being developed to test them in animal models. Please click here to read the October, 2008 press release.

University of Nevada, Reno -- Dean Burkin, PhD – Reno, NV
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 has used his assay to search two compound libraries containing FDA-approved drugs and natural products. He has found three compounds 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 —Philadelphia, PA
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. Three compounds have been identified which will be tested in DMD mice. 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 -- Seattle, WA
Phosphodiesterase Inhibitors
Dr. Froehner tested 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 cardiac muscle functions in the mouse model. Dr. Froehner also showed that PDEs may prevent heart damage in older mice. Based on promising results, this compound is being moved into human clinical trials at Johns Hopkins University. Please click here to read about the results.

Small Molecules/Novel Therapeutics

Project Catalyst – Sout h Plainfield, NJ
High-Throughput Screening for new drugs
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 from hundreds 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 2011. For more information, please click here.

Summit plc (formerly VASTox plc) – Oxfordshire, 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, SMTC 1100 also known as BMN 195 will be tested in a clinical trial some time next year. Please click here to read the press release.

Biologicals

Brown University -- Justin Fallon, PhD – Providence, RI
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 up regulate 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. Funding from Charley’s Fund and the Nash Avery Foundation has led to Dr. Fallon securing a $4MM U01 grant from the NIH.

University of Minnesota - James Ervasti, PhD -- Minneapolis, MN
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 be 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 optimal dosage, frequency of administration, and mode of delivery of TAT-utrophin. In addition, Dr. Ervasti is investigating ways to scale production of TAT-utrophin in preparation for preclinical safety and toxicology studies in animals. Please click here to read an abstract of the paper.

STEM CELL THERAPY

University of Leuven, Belgium -- Maurilio Sampaolesi, PhD - Leuven, Belgium
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.