Gene therapy makes a potent weapon against against AIDS, cancer and more

By Jay Fernandez | August 11, 2016

John Zaia, M.D.

In the past year, leading-edge gene therapy has continued to take bold steps out of the laboratory and into the realm of potentially lifesaving treatments. It is no longer beyond imagination, or even far-fetched, to envision a day when, thanks to edited genes, advanced brain tumors disappear, hemophiliacs create their own clotting factor and AIDS patients can stop taking their daily antiviral drugs.

“The field of cell-based therapy is becoming more mature,” says John Zaia, M.D., the Aaron D. Miller and Edith Miller Chair in Gene Therapy, and director of City of Hope's Center for Gene Therapy. 

In typical City of Hope style, theoretical science is getting down to business, with multiple clinical trials underway at the now 1-year-old  City of Hope Alpha Clinic. Patients are being recruited to test the safety of gene-based treatments for several cancers, as well as hemophilia and HIV/AIDS.

Leader in HIV/AIDS Research

Zaia, who's devoted much of his professional life to the AIDS battle, is especially excited about two unique stem cell transplant options that target HIV in different ways. One employs a zinc finger nuclease, or ZFN, to “edit out” the CCR5 receptor on a patient's harvested stem cells, then reintroduce them. The modified cells deny HIV its normal path to infection. 

Another approach uses a lentivirus to add re-engineered, anti-HIV ribonucleic acid (RNA) genes to stem cells, including one that disrupts CCR5. 

In targeting CCR5, Zaia and his research colleagues around the world are trying to replicate the case of the so-called “Berlin patient” whose HIV vanished after he received a stem cell transplant for treatment of leukemia. The donor's CCR5 gene had a mutation that blocked the virus. “There aren’t enough donors with that mutation to replicate the treatment on a large scale,” says Zaia, “so we have to artificially create the mutation.” 

In March 2016, the first patient received Zaia's RNA/lentivirus-based treatment under an Food and Drug Administration-approved trial, which permits only one participant at a time. Four months later the recipient is tolerating the treatment well, and the accumulated data is providing critical information.

Clinical Trials' Challenges

Finding the right patients for these trials is a special challenge. However, although the FDA now allows otherwise healthy people with HIV to participate, the risks associated with a stem cell transplant are high, because the patient must first receive an extremely potent course of chemotherapy to “create a space” for the transplanted cells. For this reason, the RNA/lentivirus trial is focused on AIDS patients with lymphoma who've completed treatment and are in remission.

“Those patients are just a better population for this trial,” says Zaia. “They're also more likely to accept the risks.” He praises those willing to come forward, lauding their “wonderful and generous humanitarian gesture.”

As encouraging as the early results may be, they are baby steps. Current therapies modify only a relatively small percentage of a patient's stem cells. Zaia hopes to one day develop a more efficient mechanism which would fortify a much larger percentage of stem cells, while protecting them from chemo's toxic effects. 

One possibility may emerge from the treatment of brain tumors performed by collaborators at the Fred Hutchinson Cancer Research Center. The usual chemotherapy drug of choice, BCNU, can be seriously toxic to bone marrow. When researchers altered a gene known as MGMT, the BCNU chemo worked more effectively and the marrow was protected.

It remains to be seen whether this approach would provide similar protection in HIV patients. The possibility is intriguing, and it's one of many reasons Zaia stands by his prediction of a year ago that a “functional cure” for HIV/AIDS (in which the virus is effectively blocked and daily drugs are no longer needed) may be just five years away. 

Making Inroads

In the meantime, gene-based technology is making inroads in other City of Hope Alpha Clinic trials.

For example, the ZFN technique is being adapted for the treatment of hemophilia in which there is a lack of clotting factor. Using the same gene-editing mechanism, researchers have been able to “cut” a normal “housekeeping” gene  and introduce a “corrected” version of the clotting factor into the liver. The process has worked in animal tests, and human trials will begin soon.

Newer gene-editing methods are emerging as well, including the much-talked-about “CRISPR” technology which can find, cut out and replace specific parts of DNA using a specially programmed enzyme. China is preparing to test CRISPR in the world's first human trials, and the FDA has approved trials in the U.S., beginning probably next year. Zaia advises caution:

“We do not have clinical trials going for CRISPR-type treatment just yet. It's much too new and we need to learn more about it. Bear in mind that it took nearly 15 years to get ZFN approved for human patients. But this could eventually be a game-changer, helping us direct our gene-editing efforts with much greater precision.”

The major partner in City of Hope's gene therapy journey continues to be California's stem cell agency, the Institute for Regenerative Medicine. CIRM grants helped establish the City of Hope Alpha Clinic and other facilities across the state, and CIRM funding is fueling many of the ongoing clinical trials, including Zaia's.

“California is ahead of the curve,” he says, “changing the culture of gene therapy.”