A robust research program is so important in the Duchenne Community and Harrison's Fund will always support promising science that we hope will make a difference to those with Duchenne.
In this section you will find basic information about some of the promising research strategies out there, the drug development process, and specific drugs in the therapeutic pipeline now.
None of us are doctors and a lot of what is included may appear a little daunting, but it will increase your understanding of Duchenne and we have done our best to find the most easily understandable descriptions of the work available.
This is centred on ultimately curing the disorder. The goal is to successfully introduce the correct code for the dystrophin protein into a muscle cell, thereby providing the cell with the recipe needed to produce dystrophin.
The challenge here is for scientists to find a means of transporting the correct genetic code for the dystrophin protein into every muscle cell in the body. Many scientists working with gene therapy are pursuing a plan to use viruses to transport this genetic information, since viruses have evolved to deposit their own genetic code into cells.
Currently, scientists can manipulate certain viruses to substitute the dystrophin code for the undesirable genetic code that the virus would naturally contain. If their theories prove correct, the manipulated virus would be injected into the patient. The result of this viral "infection" would be the successful recoding of each muscle cell in the patient's body.
Coaxing muscle cells into producing dystrophin protein without recoding dystrophin's basic genetic code is another strategy that scientists have also developed potential strategies for. These proposed cell therapies attempt to at least partially offset the muscle damage caused by the flawed genetic code.
Scientists have begun to develop cell therapy techniques that use stem cells derived from muscle. These are essentially immature muscle cells with the potential to develop into a variety of types of tissues, including skeletal muscle.
Stem cells derived from muscle are very different from embryonic stem cells, which are immature cells harvested from human embryos that can develop into any type of body tissue, and are the subject of ongoing ethical debate.
Pharmacological approaches to formulating treatments for Duchenne do not seek to repair or replace the missing genetic information in a muscle cell, or to otherwise devise mechanisms to cause the muscle cell to produce normal dystrophin. Instead, pharmacological approaches seek to treat the symptoms of Duchenne without necessarily addressing the root causes.
While pharmacological therapy may seem less dramatic than some of the newer methods being developed, pharmacological strategies also sidestep some of the most daunting obstacles associated with gene and cell therapies, most notably difficulties in achieving systemic delivery and overcoming immune response.
In 1989, scientists discovered that a protein called utrophin exists in muscle cells, principally at the junction where the nerve meets the muscle cell. Since that time, scientists have observed that utrophin could potentially operate as a substitute for dystrophin (and protect the muscle cell membrane), if muscle cells could be coaxed into producing utrophin at locations other than the neuro-muscular junction.
This strategy could perhaps lead to an effective treatment for Duchenne, using a biological process substantially simpler than those involved in gene and cell therapies.
Scientists have long theorized that the body normally contains compounds that limit muscle growth. For example, certain breeds of cattle develop substantially more muscle than ordinary cattle. Researchers have isolated the cause of this disparity to a mutation in the gene that codes for the production of a hormone called myostatin, which tends to limit muscle growth. Scientists searching for a treatment theorize that inhibiting myostatin in boys with Duchenne will cause them to develop more muscle mass initially. Ideally, this surplus will offset the muscle loss associated with Duchenne, allowing boys to retain their ability to function for a longer period of time.
Oligonucleotides are compounds used by scientists seeking to repair the deficient genetic code in the dystrophin gene. Unlike traditional gene therapy approaches, scientists are not attempting to replace the genetic code; instead, they want the muscle cell to ignore the defective part of the dystrophin gene and make a smaller (but fully intact) version of dystrophin. This research strategy is known as exon-skipping.
The intended result is that the boy's muscle cell will then produce dystrophin on its own. Scientists working with oligonucleotides hope to use a drug to "unzip" the genetic code, and then shift one side of the code to the right by a tiny degree, thereby giving the cell enough code to produce a viable dystrophin protein.
Scientists believe that this therapy could, for example, change the reading frame of a deletion in the dystrophin gene, so that an out-of-frame deletion in the dystrophin gene could be transformed into an in-frame deletion.
Their hope is that this change would cause the muscle cell to produce a form of dystrophin that is at least partially functional, which could result in a significant improvement in the quality of life for a boy with Duchenne, essentially converting his symptoms to those of the less debilitating Becker muscular dystrophy.
There remain, unfortunately, two major drawbacks to oligonucleotide therapy. First, scientists have encountered the same systemic delivery problems encountered in devising gene therapy strategies. Second, the effects of oligonucleotides wear off quickly (in only a matter of weeks), so subjects would need to repeat the oligonucleotide therapy frequently.
Here we will focus on the two most popular animal models related to Duchenne, the mdx mouse and canine X-linked muscular dystrophy.
the mdx mouse
The mdx mouse, while not a precise model of human disease, is studied extensively by researchers interested in understanding muscle degeneration and regeneration in Duchenne. As a result, most experiments are performed on the mdx mouse.
The dystrophic mdx mouse has a point mutation within its dystrophin gene. This mutation has changed a codon representing glutamine amino acid to one representing thymine amino acid. This single amino acid change causes the cell's machinery to stop; when this happens, the synthesis of dystrophin stops prematurely (known as premature stop codon). As a result, the mouse has no functional dystrophin in its muscles.
Early in life, the mdx mouse exhibits phases of marked skeletal muscle degeneration and subsequent regeneration; as it ages, certain muscle types such as the diaphragm show weakness and increased fibrosis.
canine x-linked muscular dystrophy (CXMD, Golden Retriever MD, or GRMD)
A canine X-linked muscular dystrophy (GRMD) has been identified in a line of golden retrievers. As in Duchenne patients, the muscles of CXMD dogs lack dystrophin. These dogs develop severe weakness and muscle atrophy at about six to eight weeks of age. Degeneration of muscle fibers is common and heart problems are also present.
The GRMD represents the best model for Duchenne patients in terms of size and pathological expression of the disease.
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