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Making gene therapy more effective

A new process for tagging genes could allow gene therapy to be applied to disorders such as muscular dystrophies and spinal muscular atrophy. Dr. Graham Dellaire, Dalhousie Medical School’s Cameron Research Scientist in Cancer Biology, explains his team’s discovery and how it could make gene therapy more effective.

The Problem

Gene therapy allows scientists to correct genetic disorders by replacing defective or missing genes in cells with transplanted normal genes. But it’s an expensive and time consuming process.

In the last decade, though, the discovery and refinement of a technique know as CRISPR (it stands for Clustered Regularly-Interspaced Short Palindromic Repeat) has made gene therapy easier, cheaper and faster, and its use in genome editing was deemed the top scientific breakthrough of 2015 by the American Association for the Advancement of Science. Still, CRISPR hasn’t cleared all gene therapy hurdles: “Up to now, CRISPR has been used to treat diseases that affect parts of the body comprised of cells that divide, like blood,” says Dr. Dellaire. “Researchers haven’t been able to apply CRISPR in non-dividing cells like muscle and brain tissue,” which are involved in diseases such as muscular dystrophy and spinal muscular atrophy.

The Approach

In order to apply CRISPR in non-dividing cells, researchers need to activate a cellular process called homologous recombination. Essentially, the process lets non-dividing cells behave like those that divide, allowing a cell’s genes to be manipulated and rearranged with high fidelity.

“Without reactivating the homologous recombination process, CRISPR would do more harm than good by making DNA deletions and insertions rather than correcting faulty genes,” explains Dr. Dellaire.

Dr. Daniel Durocher and his team at Mount Sinai Hospital’s Lunenfeld-Tanenbaum Research Institute in Toronto recently found a way to turn on the recombination process needed to perform gene editing in non-dividing cells. Up until that point, precise gene editing in these cells was thought to be impossible. “Dr. Durocher’s breakthrough was profound, but he and his team needed a way to prove their process,” says Dr. Dellaire. “That’s where we came in.”

The Solution

“We came up with a fluorescent tagging technique to identify when gene targeting has been successful in a cell—even in those that don’t divide,” says Dr. Dellaire. The technique shows a precision gene editing event when the cell being worked on turns green and a ring appears around its nucleus. Tens of thousands of cell samples can be screened this way, allowing researchers to keep improving gene therapies.

The Implications

This new knowledge will enable gene therapy to be applied to disorders of the musculoskeletal and nervous system—systems made up of non-dividing cells. “At this stage, getting non-dividing cells to behave like dividing cells is only safe to do in a lab environment,” explains Dr. Dellaire. “We’re trying to identify molecules that will take the place of these man-made genetic manipulations. Our hope is to one day make gene therapy a reality for diseases of non-dividing cells such as muscular dystrophies like myotonic dystrophy, and nervous disorders like spinal muscular atrophy where the faulty genes have been identified.”