Working to Fix the Genetic Cause of Disease

From Bench to Bedside

Doctors at Seattle Children’s have developed groundbreakingtools that promise to fix the genetic causes of disease. Nowthey seek funding to turn the tools into cures.

Dave Rawlings

In the clinic office and in the lab, Dr. Dave Rawlings is driven to advance the field of gene repair because of its potential to bypass the side effects ofcurrent treatments for life-threatening illnesses like AIDS, cancer and autoimmune deficiencies.

Imagine a prowler casing a neighborhood, looking for away into a home. That’s essentially what HIV, the humanimmunodeficiency virus that causes AIDS, does: It movesthrough the bloodstream trying to gain entry to T-cells – the primary warrior cells of the immune system. The opendoor HIV seeks is a protein called CCR5, a special receptoron the T-cell’s surface. Once the virus gains entry, it hampersa T-cell’s ability to do its job, leaving people vulnerable toinfection and disease – and enabling HIV to spread.

Now imagine you can lock that door forever. The viruscan’t enter the T-cells and interfere with the immune systemand the body can fight off the infection.

That vision is getting closer to reality thanks toDrs. Dave Rawlings and Andy Scharenberg at SeattleChildren’s. Working with colleagues at the University ofWashington and Fred Hutchinson Cancer Research Center,they have figured out how to modify genes and knock theCCR5 receptor off T-cells. They can make it work in the lab – now they want to turn it into an effective therapy for peoplewho have AIDS.

It’s just one application for a promising biological “toolkit”they developed to modify genes – an important advance forthe emerging field of gene editing that promises to curechronic, debilitating diseases like AIDS.

Creating new ways to modify genes

Andy Scharenberg

Easing life for patients facing
life-threatening illnesses spurs
Dr. AndyScharenberg to
develop less intrusive treatments.

Genes are the basic building blocks of DNA. They tell a cellhow to behave and what to do. Advances in understandingthe human genome have sped up researchers’ ability toidentify the genes responsible for a growing number ofdiseases and birth defects.

“Being able to identify the genetic cause is like findingthe bottleneck in the system,” says Rawlings, a pediatricimmunology specialist. “It got us thinking ‘how can we clearthe jam and eliminate the problem rather than just treat thesymptoms?’”

About a decade ago, he and Scharenberg beganassembling several teams of experts from differentdisciplines with a common vision: to create cutting-edgebiological tools that treat illnesses of the blood. Their workkicked into high gear in 2007 with a five-year, $24-millionboost from the National Institutes of Health (NIH) to fundthe Northwest Genome Engineering Consortium (NGEC) and develop the tools needed to modify genes. One ofNGEC’s great successes was creating homing endonucleasesthat can find exact locations along the DNA and preciselycut within specific genes.

Several other organizations around the world are alsoworking to develop new methods of gene repair, butRawlings thinks the tools created here are more efficientand safer.

“We started with nature’s scissor to build our homingendonucleases – it’s a naturally occurring enzyme thatevolved in fungus over millions of years with the solepurpose of cutting a DNA sequence and inserting its ownDNA,” he says. “Our process also includes a second enzymethat chews away just a bit of the DNA so it can’t repair itselfexactly as it was. This allows levels of gene editing that arepreviously unprecedented.”

AIDS and what else?

The tools developed by the NGEC have potential to improvethe immune system’s ability to fight many diseases, includingleukemia and brain cancer. For example, Dr. Mike Jensen and his team are genetically modifying T-cells so they canrecognize cancer cells as dangerous and eliminate them.But cancer cells are smart and they send a signal to the T-cells, telling them to stop working. Scharenberg andRawlings figured out how to prevent the cancer cells fromsending the “stop” message to the engineered T-cells, thusenabling them to do their work better.

What’s the holdup?

Like many researchers whose laboratory work has madepromising discoveries, Rawlings and Scharenberg are at aprecarious financial juncture in their journey: if they can’tsecure ample funding they will be unable to translate theirexciting scientific achievement into viable new therapies.

“We’re on the cusp of changing what’s possible... Now it’s time to take these tools and makesomething that helps people.”

Dr. Andy Scharenberg

With funding to move into human clinical trials, a cure forHIV could come to fruition within three to five years. Yet theorganizations that typically fund biomedical research offerlimited support for the work needed to move basic sciencefrom the laboratory to the bedside of real patients.

“We’re on the cusp of changing what’s possible. We’veshown in the lab that we can now edit whatever gene wewant to,” says Scharenberg. “Now it’s time to take thesetools and make something that helps people.”