Genetics of Duchenne Muscular Dystrophy (DMD): Gene Editing and Potential Therapeutic Approaches

, Fact-checked by: Dr. Renu B., PhD / 【┘】Last updated on February 10, 2024
dmd gene editing

Duchenne muscular dystrophy (DMD) is a severe kind of muscular dystrophy. This disease mainly affects boys and leads to worsening muscle weakness, which can eventually cause serious health problems and early death.

This health condition happens due to changes in the DMD gene, which plays an important role in keeping our muscles strong and functional.

Most boys with DMD have inherited a faulty DMD gene from their mothers through the X chromosome, although in some cases, new mutations can occur randomly.

This disease significantly affects not only patients but also their families and society as a whole. Patients with DMD often face issues with mobility, breathing, heart conditions, cognitive skills, and other complications.

Sadly, there is no cure yet for DMD, but we do have DMD management options that can slow the disease’s progression.

The need for innovative Duchenne therapy is more urgent than ever, and one of the most promising approaches we’re seeing is DMD gene therapy. This approach looks at modifying the defective DMD gene directly.

However, while it offers a lot of promise, it also comes with a set of challenges, such as safety, efficiency, and ethical concerns.

This article will provide you with a detailed understanding of DMD, its genetic basis, available treatments, and the potential of gene therapy for Duchenne Muscular Dystrophy.

Understanding DMD

Symptoms of DMD

DMD usually begins to show symptoms between ages 2 to 4, though the symptoms can vary based on the type and location of the mutation in the DMD gene.

The first signs of DMD are muscle weakness and loss of muscle mass, starting in the legs and pelvis and gradually spreading to other parts of the body.

This can affect a patient’s ability to perform regular activities such as standing up, walking, and climbing stairs.

Progression of DMD

DMD is a progressive disease that worsens over time. It starts with muscle weakness in early childhood, leading to mobility issues, breathing problems, and heart conditions by late childhood.

By adolescence and adulthood, patients often become entirely dependent on wheelchairs and face life-threatening complications.

As the disease progresses, it leads to more severe symptoms, including spinal curvature and gastrointestinal problems.

Current Diagnostic Procedures

To diagnose DMD, doctors will check for signs of muscle weakness, get a family history of muscular dystrophy, measure protein levels in the blood that may indicate muscle damage, and identify the specific mutation in the DMD gene through genetic tests.

Genetics of DMD

Duchenne Muscular Dystrophy (DMD) is a genetic disorder resulting from mutations in the DMD gene, crucial for producing dystrophin—a protein vital for muscle strength and function. These mutations can be inherited or occur spontaneously, leading to the absence of dystrophin, which is essential for protecting muscles from injury during everyday activities.

Is DMD Inherited?

Duchenne Muscular Dystrophy (DMD) is a genetic disorder predominantly affecting boys, characterized by rapid muscle degeneration. It’s inherited in an X-linked recessive manner through mutations in the DMD gene. While often seen in families with a history, it can also manifest in individuals without any known familial predisposition.

This means that boys inherit the faulty DMD gene from their mothers. Girls can also get DMD, but that is very rare as they would need to inherit two faulty DMD genes, one from each parent including an affected father.

Mutation types in DMD and their implications

DMD is caused by mutations in the DMD gene, which leads to the production of a faulty protein called dystrophin. The majority, 60-70%, are deletion mutations, followed by 20% being point mutations, small deletions, or insertions, and 5-15% as duplications. These mutations lead to the disruption of the dystrophin protein, essential for muscle function.

So, different types of mutations can cause DMD, and each type can affect the severity of the disease.

Some mutations completely stop the production of dystrophin, while others allow for some dystrophin production.

The “reading frame rule” can often predict the severity of DMD. Mutations that maintain the reading frame produce partially functional dystrophins, leading to milder forms of the disease.

Mutations that disrupt the reading frame prevent the production of functional dystrophins, causing more severe forms of DMD.

However, there are exceptions to this rule, and sometimes alternative splicing can result in partially functional dystrophins even with disruptive mutations.

Mutations like in-frame deletion/duplication or a missense mutation that does not have a major effect on the function of protein cause its milder form, called Becker muscular dystrophy (BMD).

Current Management of DMD and Their Limitations

Steroids and Side Effects

People with Duchenne Muscular Dystrophy (DMD) often take steroids like prednisone or deflazacort as part of their treatment. These medicines help delay muscle weakness and improve muscle strength.

However, there can be many side effects, like weight gain, mood swings, high blood pressure, and more. Doctors are still figuring out the best dose and timing for giving these steroids to DMD patients.

Physical Therapy and Its Limits

Physical therapy is another way to help people with DMD. This can involve a range of exercises to help maintain movement, prevent complications, and improve quality of life.

For example, stretching can help maintain flexibility, and aerobic exercises can improve heart health. There are also special trainings to help with daily tasks like getting dressed or going to the toilet.

However, physical therapy can’t stop DMD from getting worse or bring back the missing protein in muscle cells. It can also become less useful as DMD gets worse and the patient becomes more dependent on machines for breathing or heart function.

Assistive Devices and Surgery

Some people with DMD might use devices like braces or casts or have surgery to manage complications of the disease. For instance, surgery might be needed to fix severe muscle contractions, bone fractures, or a curved spine.

Surgery can bring some relief and improve the quality of life for DMD patients. However, surgery also has risks, like complications from anesthesia and other problems after surgery.

Despite these muscular dystrophy treatments, the search for better options continues. Some DMD clinical trials are exploring gene therapy for Duchenne Muscular Dystrophy.

In DMD gene therapy, scientists are trying to correct the gene for muscular dystrophy, which might be a new avenue for Duchenne therapy.

Gene Editing for DMD

Genetic diseases happen when there are mistakes or changes in your DNA. But with gene editing, scientists can correct these mistakes by replacing them with normal, healthy DNA. It’s a bit like correcting a typo in a book so the sentence makes sense again.

Think of gene editing as a type of biological “spell-check” for your body. This process allows scientists to change, add, or even remove parts of your DNA, which is the blueprint that tells your body how to work.

These changes are super specific, allowing scientists to pinpoint a particular part of your DNA to work on. They use special proteins, like tiny scissors, to cut out the bad parts of your DNA and replace them with good ones.

Key Technique (CRISPR/Cas9)

Scientists use several methods for gene editing, but one of the most popular ones right now is called CRISPR/Cas9. This technique was discovered in 2012 and has been developed further since then.

It uses a pair of molecular scissors (Cas9) guided by a special molecule (RNA) that tells the scissors where to cut the DNA.

Success Stories So Far

Gene editing has shown promise in treating several genetic diseases. Scientists have used it to fix genetic mistakes that lead to diseases like sickle cell anemia, cystic fibrosis, hemophilia, and Duchenne muscular dystrophy (DMD).

Some of these gene editing treatments have even made it to clinical trials, which is the stage where they’re tested in humans.

For Duchenne Muscular Dystrophy (DMD)

Many studies have shown that gene therapy could be a promising DMD treatment. In lab animals, scientists have used several gene editing techniques to fix the genetic mistakes causing DMD, which improved muscle function in these animals.

Some of these methods have also been tested in human cells in the lab, and the results look promising so far.

Other Potential Therapeutic Approaches

While there’s currently no cure for DMD, scientists are looking into several treatment options to either bring back dystrophin or slow the disease progression. Here are a few other approaches:

Gene Therapy

Gene therapy is a method that attempts to provide a healthy DMD gene or a modified version of it to the muscle cells of those suffering from DMD, using a viral vector as a transport vehicle.

The aim is to allow the production of dystrophin or a functional substitute that can prevent or reduce muscle damage.

This kind of Duchenne therapy has shown hopeful results in DMD animal models and some DMD clinical trials. For example, a phase 2 trial using a viral vector to give a shortened version of the dystrophin gene called microdystrophin reported improvements in muscle strength and function in people with DMD.

But, gene therapy still faces some challenges, like the limited capacity of viral vectors, the body’s defense response against the vector or the new gene, and the inconsistent gene expression among different muscles.

Stem Cell Therapy

Another approach for DMD treatment is stem cell therapy, aiming to replace the damaged muscle cells in those suffering from DMD with healthy ones that come from stem cells. Stem cells can self-renew and differentiate into various cell types.

Scientists have explored different sources of stem cells for DMD treatment, like bone marrow cells and pluripotent stem cells. Stem cell therapy has the potential to restore dystrophin expression and muscle regeneration in those with DMD.

However, this approach also faces some challenges, like the low efficiency of getting stem cells into muscles, the risk of immune rejection or tumorigenesis, and ethical issues linked with some stem cell sources.

Anti-inflammatory and muscle-enhancing drugs

Another method for DMD treatment is to use drugs that can reduce inflammation and improve muscle function.

Inflammation contributes a lot to muscle damage and fibrosis in DMD, and anti-inflammatory drugs like glucocorticoids have shown to delay the disease progression and improve the quality of life for those with DMD.

But these drugs also have serious side effects like weight gain and growth retardation. Therefore, researchers are developing alternative anti-inflammatory drugs with fewer side effects for DMD treatment.

Drugs that can enhance muscle growth and strength are also being investigated. For instance, drugs that target the myostatin pathway, which inhibits muscle growth, have been shown to increase muscle mass and function in animal models of DMD and in some clinical trials.

Ethical, and Legal Considerations

While the ongoing advancements in gene therapy, stem cell therapy, and other treatments for Duchenne Muscular Dystrophy (DMD) offer hope for improved quality of life and potential cure, they also raise several ethical, legal, and societal considerations.

Ethical Issues

From an ethical perspective, gene and stem cell therapies raise significant questions. For instance, gene editing raises questions about potential misuse or unintended consequences.

While the technology may be aimed at correcting a genetic disease, it’s also possible that the technique could be used in ethically questionable ways, such as ‘designer babies’.

Also, should access to this potentially costly treatment be granted based on need, or would only those who can afford it be able to benefit?

Stem cell therapy, particularly the use of embryonic stem cells, triggers debates over the moral status of embryos. There are concerns that the use of these cells may devalue human life, as they are typically derived from unused embryos from in vitro fertilization.

Legal Considerations

The legal landscape surrounding gene and stem cell therapies is complex and varies by region and country. There is a need for regulations that protect patients from potential harm and, at the same time, do not stifle scientific advancement.

Legislation needs to ensure that all potential therapies are thoroughly tested for safety and efficacy before being introduced to the public.

Regulations regarding the patenting and pricing of gene and stem cell therapies are also essential to ensure fair access to these treatments.

Key Points

  • Duchenne Muscular Dystrophy (DMD) is a severe muscle disease caused by gene changes that lead to a lack of the vital protein called dystrophin.
  • Gene editing, a new tool that can alter the DNA in living cells, holds the promise of correcting the gene changes causing DMD.
  • This promising technique has shown positive results in preclinical trials using animal models of DMD and is expected to move towards testing in humans soon.
  • As we move forward with gene editing, it’s important to consider and address the ethical, legal, and societal questions that it raises.
  • Everyone has a role to play in the fight against DMD – from patients and their families, to researchers, and funding organizations.

FAQs

Does DMD run in families?

Duchenne muscular dystrophy (DMD) is a genetic condition that primarily runs in families with an X-linked recessive inheritance pattern. This means that females, who have two X chromosomes, are often carriers of the mutation without showing severe symptoms. Males, with one X chromosome, are more likely to express the full phenotype of DMD if they inherit the mutated gene.

Who is most at risk for DMD?

Boys are significantly more at risk for developing Duchenne muscular dystrophy (DMD) because they inherit only one X chromosome, which comes from their mother. If this X chromosome carries the DMD mutation, the boy will develop the condition. Females can be carriers and may show mild symptoms due to the presence of a second, typically unaffected, X chromosome.

How can a boy get DMD if his mother is not a carrier?

A boy can still get DMD if his mother is not a known carrier due to spontaneous/sporadic mutations in the DMD gene that can occur in the egg before conception or early in embryonic development. These new mutations account for approximately one-third of DMD cases, where there is no family history of the disorder.

Can females get Duchenne muscular dystrophy?

While rare, females can develop Duchenne muscular dystrophy (DMD) if they have abnormalities in both of their X chromosomes or in certain cases of X chromosome monosomy. However, most female carriers are asymptomatic or display only mild symptoms due to X chromosome inactivation, which can provide a protective effect against the full manifestation of DMD.

Can you get DMD from your father?

DMD cannot be inherited directly from the father to his sons because it is an X-linked condition, and males contribute a Y chromosome to their male offspring. However, a father can pass the mutated gene to his daughters, making them carriers who might later pass the gene to their own sons.

What is the life expectancy of someone with DMD?

Advancements in medical care have significantly improved the life expectancy of individuals with Duchenne muscular dystrophy (DMD). While life expectancy varies, many people with DMD now live into their 30s and beyond, thanks to better respiratory, cardiac care, and supportive therapies.

Can a man with DMD have children?

Men with Duchenne muscular dystrophy (DMD) can have children, although their fertility may be affected by their condition. Genetic counseling is recommended to understand the risks of transmitting the disorder, as all daughters of affected men will be carriers of the condition.

Why is it unlikely for a girl to get DMD?

It’s unlikely for a girl to get DMD because females have two X chromosomes, and the presence of a healthy X chromosome usually compensates for the mutated gene on the other X chromosome. This genetic backup helps prevent the full-blown development of DMD in females, making them carriers more often than affected individuals.

Why do boys inherit DMD more than girls?

Boys inherit DMD more than girls due to the X-linked nature of the mutation causing the condition. Since boys have only one X chromosome, a single copy of the mutated gene on this chromosome will result in DMD. Girls, with two X chromosomes, must have the mutation on both to show severe symptoms, a much rarer scenario.

What are the odds of getting Duchenne muscular dystrophy?

The odds of a boy being born with Duchenne muscular dystrophy (DMD) are approximately 1 in 3,500 worldwide. The risk for offspring of carrier mothers is 50% for sons to inherit DMD and 50% for daughters to become carriers, highlighting the importance of genetic counseling for families with a history of DMD.

Who is the carrier of muscular dystrophy?

The carrier of muscular dystrophy, particularly in the context of X-linked conditions like DMD, is typically the mother. Carriers have one normal and one mutated X chromosome, with a 50% chance of passing the mutated gene to their children. Female carriers may exhibit mild symptoms or none at all, depending on X chromosome inactivation patterns.

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