9/1/2023 Bethan Owen
A team of researchers including bioengineering professor Pablo Perez-Pinera and bioengineering professor and Dean of The Grainger College of Engineering Rashid Bashir have published a paper on the potential of CRISPR-SKIP gene editing to address Duchenne muscular dystrophy.
Written by Bethan Owen
A team of researchers including bioengineering professor Pablo Perez-Pinera and bioengineering professor and Dean of The Grainger College of Engineering Rashid Bashir have published a paper on the potential of CRISPR-SKIP gene editing to address Duchenne muscular dystrophy.
This paper, titled “Targeting Duchenne Muscular Dystrophy by Skipping DMD Exon 45 with Base Editors” was published in the journal Molecular Therapy – Nucleic Acids.
Duchenne muscular dystrophy is a genetic disorder which results in progressive loss of muscle function at a young age. This condition, which is often diagnosed in early childhood, causes muscle weakness which starts in the core muscles and gradually affects other muscles in the body, including the heart and respiratory muscles. Duchenne muscular dystrophy causes a significantly reduced life expectancy and currently has no cure.
While there is work to be done in the field of gene editing before an effective treatment can be produced, Perez-Pinera’s research in gene editing–specifically working with CRISPR-SKIP–shows promise in understanding how to treat Duchenne.
Duchenne is frequently caused by sections of genetic code, or exons, that have been damaged or erased by genetic deletion within the dystrophin gene. These faulty exons cause a shift in the translation of the genetic code, leading to a shortened, non-functional protein. Because so many different mutations can cause Duchenne, CRISPR-SKIP is uniquely suited for the task of repairing the protein; rather than attempting to correct every flaw, the SKIP method introduces modifications in genomic DNA that change how the cells interpret the genetic code when making proteins.
“In the case of Duchenne muscular dystrophy, there are hundreds of mutations that can cause the disease,” said Perez-Pinera. “Developing therapies to correct each one of them would be a daunting and particularly expensive task. Correcting groups of mutations by exon skipping is preferable.”
In their research, Perez-Pinera and his team used a genetic model that lacked exon 44 in the dystrophin gene, leading to all exons after 43 being out of frame. By using CRISPR-SKIP to bypass exons 44 and 45, they were able to recover expression of all exons after 46, which allowed most of the protein to be expressed. The protein produced by this treatment lacked a few amino acids, but retained enough functionality to change the course of the disease.
It’s an exciting result, and in addition to Duchenne, the CRISPR-SKIP method has the potential to advance treatment of several different neural disorders, including Alzheimer’s disease, Parkinson’s disease, and more.
“We hope that through extensive optimization this will one day become a treatment for Duchenne and other terminal diseases,” said Michael Gapinske, a former bioengineering graduate student who led the work. “I also hope that the work and its limitations will inform the development of better base editing therapies in the future.”
The study is currently in the proof of concept stage, and will require extensive additional research before it can be used in humans. Perez-Pinera looks forward to continuing the work.
“The next logical step is to optimize editing using mouse models of the disease to which we will deliver improved, more effective versions of the base editing tools,” he said. “We are currently working in these directions in the lab.”