Research

Scientists around the globe are conducting intense research to discover and develop effective treatments

DMD mutations: why aren't the Duchenne boys (and girls) able to produce dystrophin?

The dystrophin gene has 79 exons

 

The blueprint for dystrophin is embedded in the DMD gene. The parts containing the genetic information the cell needs to generate proteins are called "exons". The DMD gene has 79 exons.

 

These exons fit together like pieces of a jigsaw puzzle and form the genetic code for the dystrophin protein, a protein that helps keep muscle cells intact.

When there is a mutation...

 

Duchenne patients have mistakes (mutations) in their DMD gene. The most common mistake is that one or more exons are missing from the gene (= a deletion). 

 

As a result the genetic code is broken and the consequence is that the blueprint becomes unreadable after the missing (or mutated/duplicated) exon(s) and the translation into dystrophin is stopped prematurely.

 

Oscar's mutation is on exon 24 and it's a microdeletion. It means that a small part of that exon is missing. Unfortunately it still prevents him from producing dystrophin. It's not a common mutation, which isn't good news since laboratories are more interested in common mutations. Fortunately some of the promising research projects do not depend on the location of the mutation (see below). 

Promising research strategies

  • gene therapy > 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.

 

  • cell therapy > 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 therapies > 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.

 

  • utrophin upregulators > 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.

 

  • myostatin inhibitors > 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.

 

  • exon-skipping > 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.

https://harrisonsfund.com/the-research.php

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