Study of the Week: New Gene Editing Approach to Treat Duchenne Muscular Dystrophy

Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.


This week’s study is…

Efficient precise in vivo base editing in adult dystrophic mice

We previously published about this research in a story titled “Modified Base Editing Could Correct DMD Mutations” which can be found here. The study was originally published in the science research journal Nature Communications. You can view the full text of the study here.

This research team was affiliated with The Ohio State University Wexner Medical Center and College of Medicine.

What Happened?

The promise of gene therapy and gene editing to treat genetic disorders has continued to grow steadily in recent years, with several gene therapies having been approved for use. Gene editing technologies such as CRISPR/Cas9 have also made headlines as a future approach to treating and even curing genetic illness. In this study, the research team developed and evaluated a new form of base editing that has the potential to correct mutations linked to Duchenne muscular dystrophy and certain cardiovascular diseases.

Base editing is an advanced form of gene editing that can potentially allow for precise adjustments in genes that can correct mutations; however, base editors are large and they can cause off-target effects, making in vivo editing a challenge. The researchers in this study modified an NG-targeting adenine base editor (iABE-NGA) in an attempt to overcome these limitations. The feasibility of this modified base editor was then tested using a widespread mouse model of Duchenne muscular dystrophy (DMD). 

The editor was delivered using an adeno-associated viral vector (AAV9-iABE-NGA). The approach saw improvements in the mice, such as better function and restoration of dystrophin. The iABE-NGA offers advantages over earlier technologies such as CRISPR, which cut the DNA. At 10 months, there was no clear toxicity detected by the researchers, and off-target activity appeared low. The scientists saw the restoration of dystrophin expression in 15 percent of skeletal muscle cells and 95 percent of heart cells (cardiomyocytes).

About Duchenne Muscular Dystrophy (DMD)

Duchenne muscular dystrophy is a neuromuscular disease, and it is one of the more severe types of muscular dystrophy. It is characterized by progressive muscle weakness that usually begins around age four and worsens quickly. As an X-linked genetic disease, males are mostly affected, with females only occasionally displaying mild symptoms. The disease is caused by mutations of the dystrophin gene. Symptoms of Duchenne muscular dystrophy include falling, abnormal walking posture, eventual loss of walking ability, muscle fiber deformities, intellectual disability (not in all cases), enlargement of the tongue and calf muscles, skeletal deformities, muscle atrophy, heart abnormalities, and difficulty with breathing. Treatment includes a variety of medications and therapies that can help alleviate symptoms and slow disease progression. Lifespan is usually into the thirties with good care. Better treatments for this disease are urgently needed. To learn more about Duchenne muscular dystrophy, click here.

Why Does it Matter?

First and foremost, the findings from this study represent both an improvement in the base editing system and a potential avenue for a future therapy that could help treat Duchenne muscular dystrophy and genetic cardiomyopathies.

“It has significant implications for clinical translation. This type of base editing does not require repeated treatment since it directly modifies the genetic code and produces a long-lasting therapeutic effect. Since it also doesn’t cut the genomic DNA, which happens with CRISPR, there are no large DNA deletions and chromosomal rearrangements.” – lead author Renzhi Han

The editing efficiency with this approach was especially noted in the heart, which means that the approach could be used for a wide range of genetic diseases that affect this vital organ. There is still much research to be done before the method could be implemented as a treatment, however. This first step following these results would most likely be a larger scale mouse or other animal model study that could serve as further preclinical testing. 

Still, the findings are a cause for hope that the outcomes for patients with genetic cardiomyopathies and Duchenne muscular dystrophy could see real improvements in the future.

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