CRISPR used to halt DMD progression in dogs

UT Southwestern scientists have used CRISPR gene editing to halt the progression of Duchenne muscular dystrophy (DMD) in dogs.

The study, published in Science, has shown improvement in the muscle fibres of dogs with DMD.

Researchers used a single-cut gene-editing technique to restore dystrophin in muscle and heart tissue by up to 92% of normal levels. Scientists have estimated a 15% threshold is needed to significantly help patients.

DMD is a common fatal genetic disease in children, caused by a mutation that inhibits the production of dystrophin, a protein critical for muscle function.

“Children with DMD often die either because their heart loses the strength to pump or their diaphragm becomes too weak to breathe,” said Dr Eric Olson, Director of UT Southwestern’s Hamon Center for Regenerative Science and Medicine.

The Science study establishes the proof of concept for single-cut gene editing in dystrophic muscle and represents a major step towards a clinical trial. Already Dr Olson’s team has corrected DMD mutations in mice and human cells by making single cuts at strategic points of the mutated DNA.

The latest research applied the same technique in four dogs that shared the type of mutation most commonly seen in DMD patients. Scientists used a harmless virus called adeno-associated virus (AAV) to deliver CRISPR gene-editing components to exon 51, one of the 79 exons that comprise the dystrophin gene.

CRISPR edited the exon, and within several weeks the missing protein was restored in muscle tissue throughout the body, including 92% correction in the heart and 58% in the diaphragm, the main muscle needed for breathing.

“Our strategy is different from other therapeutic approaches for DMD because it edits the mutation that causes the disease and restores normal expression of the repaired dystrophin,” said Dr Leonela Amoasii, lead author of the study and Assistant Instructor of Molecular Biology in Dr Olson’s lab. “But we have more to do before we can use this clinically.”

Dr Amoasii works in the Olson lab at UT Southwestern Medical Center. The study led by Dr Olson and Dr Amoasii demonstrates how gene editing halted the progression of Duchenne muscular dystrophy in dogs.

The lab will next conduct longer-term studies to measure whether the dystrophin levels remain stable and to ensure the gene edits do not have adverse side effects.

Dr Olson hopes the next step beyond dogs is a clinical trial, which would be among several that UT Southwestern’s gene therapy centre aims to launch in the coming years to address numerous deadly childhood diseases.

In the meantime, Dr Olson’s recent work has spawned a biotechnology company, Exonics Therapeutics Inc., which is working to further optimise and bring this technology to the clinic. Exonics intends to extend the approach to additional DMD mutations, as well as other neuromuscular diseases. Exonics has licensed the technology from UT Southwestern.

Image caption: Dr Leonela Amoasii works in the Olson lab at UT Southwestern Medical Center. Drs Olson and Amoasii led a study that demonstrates how gene editing halted the progression of Duchenne muscular dystrophy in dogs.