How To Fix Duchenne Muscular Dystrophy

Scientists at the University of California, Berkeley, have engineered a new way to deliver CRISPR-Cas9 gene-editing technology inside cells and have demonstrated in mice that the technology can repair the mutation that causes Duchenne muscular dystrophy, a severe muscle-wasting disease. A new study shows that a single injection of CRISPR-Gold, as the new delivery system is called, into mice with Duchenne muscular dystrophy led to an 18-times-higher correction rate and a two-fold increase in a strength and agility test compared to control groups.

Since 2012, when study co-author Jennifer Doudna, a professor of molecular and cell biology and of chemistry at UC Berkeley, and colleague Emmanuelle Charpentier, of the Max Planck Institute for Infection Biology, repurposed the Cas9 protein to create a cheap, precise and easy-to-use gene editor, researchers have hoped that therapies based on CRISPR-Cas9 would one day revolutionize the treatment of genetic diseases. Yet developing treatments for genetic diseases remains a big challenge in medicine. This is because most genetic diseases can be cured only if the disease-causing gene mutation is corrected back to the normal sequence, and this is impossible to do with conventional therapeutics.

CRISPR/Cas9, however, can correct gene mutations by cutting the mutated DNA and triggering homology-directed DNA repair. However, strategies for safely delivering the necessary components (Cas9, guide RNA that directs Cas9 to a specific gene, and donor DNA) into cells need to be developed before the potential of CRISPR-Cas9-based therapeutics can be realized. A common technique to deliver CRISPR-Cas9 into cells employs viruses, but that technique has a number of complications. CRISPR-Gold does not need viruses.

In the new study, research lead by the laboratories of Berkeley bioengineering professors Niren Murthy and Irina Conboy demonstrated that their novel approach, called CRISPR-Gold because gold nanoparticles are a key component, can deliver Cas9 – the protein that binds and cuts DNA – along with guide RNA and donor DNA into the cells of a living organism to fix a gene mutation.

CRISPR-Gold is the first example of a delivery vehicle that can deliver all of the CRISPR components needed to correct gene mutations, without the use of viruses,” Murthy said.

The study was published in the journal Nature Biomedical Engineering.

Source: http://news.berkeley.edu/

How To Cure Distrophy

Researchers at Washington University School of Medicine in St. Louis have demonstrated a new approach to treating muscular dystrophy. Mice with a form of this muscle-weakening disease showed improved strength and heart function when treated with nanoparticles loaded with rapamycin, an immunosuppressive drug recently found to improve recycling of cellular waste.The investigators, including first author Kristin P. Bibee, MD, PhD, looked at a mouse model of Duchenne muscular dystrophy, the most severe inherited form of the disease. Duchenne exclusively affects boys who have to rely on wheelchairs by age 12 and die from heart or respiratory failure in their 20s. Worldwide between 1,500,000 and 2 millions individuals suffer from the disease.

The faulty gene that causes the disease prevents the body from producing dystrophin, a protein crucial for maintaining muscle cell integrity and function. The new study demonstrated that mice with muscular dystrophy, in addition to missing dystrophin, also can’t recycle cellular waste, a process known as autophagy, or self-eating.
Robert J. Boston PhotographerKristin Bibee MD PhDHolds bins of particles in the Nanoparticle formulation laboratory.A new study uses nanoparticles to treat muscular dystrophy in mice. The study’s first author, Kristin P. Bibee, MD, PhD, holds vials of nanoparticle formulations
Autophagy plays a major role in disposing of cellular debris,” said senior author Samuel A. Wickline, MD, the James R. Hornsby Family Professor of Medicine. “If it doesn’t happen, you might say the cell chokes on its own refuse. In muscular dystrophy, defective autophagy is not necessarily a primary source of muscle weakness, but it clearly becomes a problem over time. If you solve that, you can help the situation by maintaining more normal cellular function.

Some investigators are looking for ways to replace dystrophin,” said co-author Conrad C. Weihl, MD, PhD, associate professor of neurology. “But here we are focusing on the defect in autophagy. What is exciting about our approach is that there are existing drugs that activate autophagy. And by repackaging the drug on nanoparticles, we can target it specifically to muscles and correct the defect in the cells’ ability to recycle waste.”

The study appears online in The FASEB Journal.
Source: http://news.wustl.edu/