Research Focus: Cancer, Sickle Cell Disease, and "Bubble Boy" Syndrome

Dr. Donald Kohn has a vision – if he can genetically fix the root causes of certain diseases from inside the dysfunctional cells, he may uncover new and more effective therapies for such devastating maladies as sickle cell disease, “bubble boy” syndrome, and virulent forms of cancer.

Current treatments for these disorders are ineffective, and do not seek to fix what’s wrong with the cells from the inside. Using gene therapy, Kohn, a world leading expert in stem cell and translational medicine, believes he can target the root causes of these diseases, adding an improved gene that prevents red blood cells from “sickling,” putting back a missing gene that makes an enzyme to prevent severe combined immunodeficiency (SCID) or bubble boy syndrome, and engineering blood stem cells to make T-cells that can seek out and fight acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma.

“The gene therapy field has matured considerably in the last decade,” said Kohn, who serves as director of the UCLA Human Gene Medicine Program, one of the largest in the nation. Kohn is a researcher with the UCLA Broad Stem Cell Research Center and a professor of microbiology, immunology and molecular genetics and pediatrics. “Some of the initial ideas did not work, but we went back to the lab and gained a better understanding of important parts of the immune system and other biological functions and our genetic techniques have become much more advanced.”

Kohn’s studies of methods for effective gene transfer and expression have translated findings from his laboratory into gene therapy clinical trials for SCID. A clinical trial for sickle cell disease is currently being planned.

Sickle cell disease affects one in 500 African Americans and one in 1,000 to 1,400 Latinos. The genetic disease causes red blood cells to “sickle” under conditions of low oxygen, meaning they become crescent shaped and have difficulty passing through small blood vessels. Median survival is 42 years for men, 48 years for women.

Kohn hopes to alleviate the suffering of patients with sickle cell by inserting a corrective hemoglobin gene into the patient’s adult blood stem cells, keeping them from sickling. The technique would work similarly to an autologous bone marrow transplant, in which a patient receives his own bone marrow back after high-dose chemotherapy.

In this study, the blood stem cells that make the diseased red blood cells would be removed from the patient and high dose chemotherapy would be delivered to kill off the immune system. The genetically altered blood stem cells would then be given back to the patient, where they ideally will re-populate the blood supply with healthy red blood cells.

In October 2009, Kohn was awarded a $9.2 million grant from the California Institute of Regenerative Medicine, the state’s stem cell agency, with the goal of taking this leading-edge stem cell science from the laboratory and translating it into a clinical trial within four years.

“Successful use of stem cell gene therapy for sickle cell disease has the potential to provide a more effective and safe treatment to a larger proportion of affected patients,” Kohn said. He and his team are now about 18 months into their project and discussions with the FDA about submitting an investigational new drug application that would lead to clinical trial are already underway.
“We’re quite optimistic that within five to 10 years we could have a new drug approved to treat sickle cell disease,” Kohn said.

In SCID, Kohn has focused his effort on a form of the disease where there is a lack of the enzyme adenosine deaminase (ADA), causing patients to be born with a severely limited or absent immune system. It is a rare disease, occurring in about one of 50,000 births, but it is devastating to families. Untreated, ADA-deficient SCID can cause death within just a few years.

A bone marrow transplant from a good sibling match can significantly increase survival rates to about 90 percent. Using marrow from an unrelated donor or cord blood gives a SCID baby about a 70 percent shot at long-term survival.

“We want to do better than that 70 percent,” Kohn said.

UCLA is the lead site for a clinical trial now underway where bone marrow is taken from the patient, who then receives one dose of chemotherapy. The blood stem cells are isolated and the gene responsible for making ADA is inserted into the blood stem cells, allowing them to produce the T-cells needed for a healthy immune system. Under the direction of Kohn, this trial is in being conducted in collaboration with the National Institutes of Health. So far, of the 10 patients treated in the Phase I trial over the last decade, all are alive, Kohn said.

In the Phase II study, which includes eight patients, all eight are still alive and doing well. The therapy works best in the youngest patients, before their bodies become too weakened by repeat infections. In one case, Kohn treated a young boy in the Phase I study at age two, and three years later, his immunity is significantly improved. "His younger sister was treated in the Phase II study beginning at age three months and is doing very well," Kohn said.

In his study of cancer, Kohn is working on a project that would harness the immune system to fight cancers of B-cell lineage, including ALL, CLL and non-Hodgkin’s lymphoma. He hopes to genetically engineer the blood stem cells that make the cells of the immune system to produce T-cells that are drawn to and attack the cancer cells. These engineered blood stem cells would potentially make these cancer-seeking T-cells forever. "Although the genetic alteration is made to all blood stem cells, the receptor that can recognize and kill the cancer is only expressed on the surface of T-cells," Kohn said.

Other methods to genetically engineer the immune system to fight cancer have focused on engineering the T-cells to seek out and kill the cancer. However, those T-cells have a shelf life of only about a month or two. Kohn is taking that idea a step further, targeting the stem cells that make the T-cells for a long-lasting, perhaps lifelong, ability to seek out and kill cancer.

“It’s only at a place like UCLA, and particularly at the Broad Stem Cell Research Center, that these types of collaborative projects can be developed and tested,” Kohn said. “We have everything from a cutting-edge medical center to great basic science programs on one campus, and the environment is cooperative and collegial and fosters the creation of leading-edge science.”