generally well tolerated. The next step was to track the fate of the genetically modified, transplanted T-cells by exposing them to the HIV virus during a temporary interruption of antiretroviral drug treatment. Six of the trial participants suspended their HIV drug regimens. The T-cells with disabled CCR5 genes survived better than the unmodified T-cells, Sangamo announced. A key aim of current HIV drugs is to maintain T-cell population numbers at normal levels.
Sangamo also revealed later tweaks to its SB-728-T therapy in data presented at an HIV/AIDS conference on Thursday. In another small early stage trial, investigators used a preconditioning treatment before the trial participants received the infusion of their genetically modified T-cells. The pre-treatment with the drug cyclophosphamide (Cytoxan), which is typically used against cancer or autoimmune diseases, helped the modified T-cells establish themselves in the body, and also enhanced the control of viral levels once antiretroviral drug treatment was suspended in some trial subjects for several weeks, investigators found.
The much-discussed star participant in Sangamo’s trials has ceased taking HIV drugs for about seven months while maintaining undetectable counts of HIV virus. In that individual, however, one of the two original copies (or alleles) of the CCR5 gene is the rare, natural variation that makes T-cells resistant to the entry of the most common form of the HIV virus. After Sangamo’s treatment, it’s assumed, both copies of the CCR5 gene were inactive in many of that individual’s T-cells—and this may be the reason why HIV levels became undetectable.
Sangamo is now planning to alter its ZFN method of editing genes to increase the chances that it can disable both copies of the CCR5 gene in future trial participants. (Every cell in the body, except for eggs and sperm, carries two sets of genes, one set inherited from each parent.)
“To make a therapy, we’ll need to knock out both alleles,” Lanphier told me Thursday during a day of back-to-back media interviews.
While gene therapy may seem to move forward by such inches, tweaks, and increments, the wider story in the Sangamo announcements this week is the growth of a set of technologies shared among a community of scientists and companies working on genetic modifications to treat a variety of different diseases.
A senior author of the New England Journal of Medicine paper about Sangamo’s first HIV trial is Carl June, a professor of immunotherapy at the University of Pennsylvania, who also drew attention at the annual meeting of the American Society of Hematology in December with the favorable results of an experimental gene therapy treatment for two blood cancers, chronic lymphocytic leukemia and acute lymphoblastic leukemia. The Swiss drug giant Novartis (NOVN) has licensed the method, Bloomberg reported from the conference.
Sangamo itself is crossing the jurisdictional lines of disease. Its pipeline includes experimental therapies for the genetically based blood disorders beta-thalassemia and sickle cell disease; in January it announced a partnership on that work with Cambridge, MA-based Biogen Idec (NASDAQ: BIIB). Sangamo is also working on potential gene-altering treatments for hemophilia A, hemophilia B, and Huntington’s Disease in a collaboration with Shire.
“ZFN could be applied to whatever gene we want,” Lanphier says.
Sangamo also isn’t alone in its pursuit of a gene therapy for HIV. Both Sangamo and Los Angeles, CA-based Calimmune have received grants from California’s stem cell research funding agency, the California Institute for Regenerative Medicine, for their work on experimental HIV therapies involving stem cells. Using different techniques, each company is genetically modifying the hematopoietic stem cells that circulate in the blood and give rise to a stable of blood and immune system cells.
In Sangamo’s treatment, the re-engineered stem cells would be re-introduced into the body through a “low-intensity bone marrow transplant,” says Geoff Nichol, Sangamo’s executive vice president of research and development. Theoretically, the modified stem cells would then produce a range of different types of blood-borne cells protected from HIV infection—not only the T-cells that are the targets of Sangamo’s completed trials using modified T-cell infusions. Other immune cells generated by genetically modified stem cells might be enabled to kill the virus, Nichol says. Sangamo plans to seek FDA permission this year for clinical trials of that method.
However, the gene therapy company that succeeds in developing a functional HIV cure may some day face competition from a longtime rival: Gilead. The kingpin of antiretroviral HIV drug sales is conducting its own research programs on potential cures for HIV infection that don’t rely on gene modification. Gilead is studying drug compounds with the potential to eradicate all vestiges of HIV in the human tissues that serve as reservoirs where the deadly virus can hide out.
