Fast Tracking Therapies for Our Boys

Many different approaches to slow down the progression of Duchenne are currently being evaluated. Some are already being tested in humans and we are hopeful that others will soon make it to clinical trials. A variety of more aggressive approaches, that might someday be a cure, are moving forward, but still further out on the horizon.

Exon-Skipping
Antisense Oligoribonucleotides (AONs): The goal of these compounds is to change a Duchenne dystrophy into a milder Becker dystrophy by sniping out exons adjacent to the mutation and then splicing them back together, creating an in-frame reading that should produce a shortened, but functional dystrophin protein. This technology does not change the DNA, but modifies the RNA during transcription.

Status: Prosensa, a Dutch biotech company has seen positive dystrophin production within the small area of muscle that was injected with their AON for exon 51. They are working towards systemic trials in 2007 or 2008. In the UK, the MDEX Consortium will begin their intramuscular trial, skipping exon 51, scheduled for March 2007.

U7 Gene Transfer
U7-small nuclear RNAs can be modified in order to instruct muscle cells to skip exons. The U7-snRNAs are delivered via an AAV (adeno-associated virus) and might provide long lasting exon skipping within the muscle cells.

Status: Luis Garcia in France has tested U-7 in mice and golden retriever dogs. A shortened dystrophin protein was successfully produced in muscle cells. This procedure requires a significant amount of the virus to get the result and it’s possible that immune suppression will be required. Dr. Garcia is working towards a Phase 1 clinical trial with Duchenne boys where exon 51 will be skipped.

Stem Cell Therapy
There are two basic types of stem cells, embryonic and adult. Adult stem cells are found in organs or tissue after birth. Embryonic stem cells are pluri-potent which means they have the potential to develop into any of the cell types found in an adult organism. Adult stem cells are called multi-potent, they have the potential to make a few cell types in the body. And recently, potential therapeutic stem cells have been taken from amniotic fluid.

Status: Dr. Giulio Cossu, director of Stem Cell Research Institute in Milan, has injected adult stem cells called mesoangioblasts, into dystrophic dogs and has seen remarkable results, with increased strength and reduced muscle damage. Mesoangioblasts are taken from the outside of small blood vessels within the muscle tissue. This therapy will most likely require immune suppression therapy. Dr. Cossu is in the process of additional pre-clinical work which will hopefully lead to clinical trials in the near future.

Gene Transfer Therapy

Viral Vector Delivery: Adeno-associated viruses and lentiviruses are two vectors that are being used in research to deliver a corrected gene into the DNA of the dystrophic muscle. These viruses are modified, the “bad” material removed, and a shortened, but in-frame dystrophin inserted. When these viruses are injected into dystrophic muscle they are able to regenerate muscle cells. The goal is to achieve a long lasting gene correction.

Status: Dr. Jeffrey Chamberlain has been working to maximize the effectiveness of this process and a delivery system of mini and micro dystrophin. Asklepios Biopharmaceutical, in collaboration with University of North Carolina and Ohio State University and supported by MDA has begun phase 1a clinical trial. Six patients received local intramuscular injections of the gene vector. No adverse reactions were observed. The results are expected to be released in 2nd or 3rd quarter of 2007.

Non-Viral Delivery: AFM and Transgene have worked for several years to deliver full length dystrophin via a non-viral system. More recently they have collaborated with Mirus to deliver the dystrophin within a plasma and injected under pressure by blocking circulation of a limb with a cuff.

Status: This system has shown to be safe in animals. Most likely this procedure would be limited to upper limbs. They will continue with pre-clinical studies and look for ways to increase the production of the plasma/dystrophin.

Pharmacalogical Therapies

During the last few years we’ve seen a plethora of possible drug therapies that could slow down the progression of Duchenne, and in some cases, actually halt the degeneration.

Up/Down Regulate Compensatory Genes: By affecting other genes in the body, scientists believe that muscle could be spared and actually encouraged to regenerate.

Utrophin is a gene that acts similar to dystrophin. By up regulating this protein, the muscle membrane could be stabilized. PTC Therapeutics and VASTox are among many organizations working on this approach.

Myostatin inhibits the growth of muscle. Many groups are involved in myostatin inhibition including Wyeth and PTC Therapeutics.

IGF-1, insulin-like growth factor is a protein that has been shown to promote muscle growth. Developing the right compound and perfecting the best delivery system will take more research. PTC Therapeutics is working on optimizing drugs for this approach.

PTC124: PTC Therapeutics is in phase 2 trial, with a drug that reads through a premature stop codon. Approximately 10% of DMD boys have this mutation. The trial results have proved to be very encouraging. At this time the patients enrolled in the clinical trial are receiving an increased dose. Many families are very anxious to see this trial move into the next phase.

Potential Steroid Replacements

Corticoid steroids have been the only therapy available to DMD boys. As much as they have helped extend ambulation and overall health of Duchenne patients, they carry with them many unwanted side effects. There are drugs that have been tested in animals and have had positive effects as good or better than steroids, without the side effects.

Losartan is a blood pressure drug which has been taken safely by 5 million people, including children. Dr. Ronald Cohn has published a paper that shows losartan to inhibit TGFb which allows for a better environment for muscle to regenerate and which also decreases the formation of fibrosis and connective tissue. This drug has the possibility to get to clinical trial quickly since it is already FDA approved for pediatric applications.

HCT1026 in a non-steroid, anti-inflammatory drug that increases nitric oxide in the muscle cells of mice. With this drug, muscle degeneration was slowed and functional improvement of strength was observed. This study was lead by Dr. Emilio Clementi in Milan, Italy.

HDAC Inhibitors, a particular class of drugs, is being investigated as a possible treatment for Duchenne. HDAC inhibitors increase the production of satellite cells.Dr. Lorenzo Puri of Burnham Institute in San Diego is experimenting with TSA, a drug under evaluation for breast cancer, as well as other FDA approved for pediatric applications.

Nutritional Supplements: These include glutamine, arginine, creatine, carnitine, green tea, protandim, and many other anti-oxidents. We will update this list and try to provide at least anecdotal results for some of these.

Summary
A single drug cure remains the challenge, but the good news is that a possible combination of therapies could be unfolding that could dramatically improve the lives of Duchenne boys. As parents of a 10 year old Duchenne boy, it can’t happen fast enough for us. We can’t stress enough how important it is for everyone concerned with Duchenne to rally together and raise the money to fund this vital research. When we receive a proposal from a scientist or a biotech company, our first questions is, “What will it take to get this to trial in half the time proposed?” The answer is usually a very large amount of money. With your help we have made tremendous strides.

Our hope for this generation of Duchenne Boys is stronger than ever. But our work is far from over. Please refer to the “How You Can Help” tab on our home page, and we sincerely thank you for your loving support.