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A new method significantly improves the ability of scientists to "edit"
faulty genes and replace damaged gene code with healthy DNA.
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Engineering a solution to genetic diseases

New study advances scientists' ability to permanently 'edit' faulty genes.

In his mind, Basil Hubbard can already picture a new world of therapeutic treatments for millions of patients just over the horizon. It's a future in which diseases like muscular dystrophy, cystic fibrosis and many others, are treated permanently through the science of genome engineering. Thanks to his latest work, Hubbard is bringing that future closer to reality.

Hubbard's research, published in the journal Nature Methods, demonstrates a new technology advancing the field of genome engineering. The method significantly improves the ability of scientists to target specific faulty genes, and then "edit" them, as in replace the damaged genetic code with healthy DNA.

"There is a trend in the scientific community to develop therapeutics in a more rational fashion, rather than just relying on traditional chemical screens. We're moving towards a very logical type of treatment for genetic diseases, where we can actually say, 'Your disease is caused by a mutation in gene X, and we're going to correct this mutation to treat it'.

"In theory, genome engineering will eventually allow us to permanently cure genetic diseases by editing the specific faulty gene(s)."

Basil Hubbard PhD, Assistant Professor of Pharmacology, University of Alberta's Faculty of Medicine & Dentistry, Alberta, Canada.

Genome engineering involves modification of an organism's specific genetic information. Just as a computer programmer edits computer code, the idea is that scientists could one day replace a person's broken or unhealthy genes with healthy ones using sequence-specific DNA binding proteins attached with DNA-editing tools. The field has made large strides in the last two decades and may revolutionize medical care.

One of the obstacles still to be addressed though, is how to ensure the proteins only affect the specific targeted genes in need of repair. With current technologies, the proteins bind and correctly edit genes the majority of the time, but more improvement is needed to insure potential errors never occur.

In the lab of David R. Liu at Harvard University, Hubbard has developed a way to reduce the possibility of off-target DNA binding with a class of gene editing proteins known as transcription activator-like effector nucleases or TALENs. His new method called DNA-binding phage-assisted continuous evolution or DB-PACE, allows researchers to rapidly evolve the TALEN proteins autonomously over time, in order to make them more specific to their gene target.

"This technology allows you to systematically say, 'I want to target this DNA sequence, and I don't want to target these others,' and it basically evolves a protein to do just that. Using this system, we can produce gene editing tools that are 100 times more specific for their target sequence."

Basil Hubbard PhD

Currently much of the research in the field of gene engineering is focused on treating monogenic diseases — or diseases of a single gene — as they're much easier to target. Diseases such as hemophilia, sickle cell anemia, muscular dystrophy and cystic fibrosis are monogenic.

While the field is still in its infancy, Hubbard says human clinical trials are already underway. If successful, he expects the first clinical applications could be in use in the next decade.

"Whereas traditional pharmaceutical drugs have a transient effect, gene editing could possibly provide a permanent cure for a lot of different diseases. We still have to overcome many hurdles but I think this technology definitely has the potential to be transformative in medicine."

Basil Hubbard PhD

Abstract
Nucleases containing programmable DNA-binding domains can alter the genomes of model organisms and have the potential to become human therapeutics. Here we present DNA-binding phage-assisted continuous evolution (DB-PACE) as a general approach for the laboratory evolution of DNA-binding activity and specificity. We used this system to generate transcription activator–like effectors nucleases (TALENs) with broadly improved DNA cleavage specificity, establishing DB-PACE as a versatile approach for improving the accuracy of genome-editing agents.

Research funding was provided by the U.S. Defense Advanced Research Projects Agency (DARPA).

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