knock out both copies of the CCR5 gene, rendering the T-cells impervious to infection by the virus.
Sangamo has been running a series of early stage trials on the T-cell modifying treatment, SB-728-T, which is its lead drug candidate. The company is encouraged by the data so far, and expects to report further results by the end of the year. Sangamo also plans to file an IND in 2014 to begin clinical trials of the SB-728 treatment on hematopoietic stem cells.
Ideally, one of these methods would duplicate the “functional cure” reportedly achieved for an HIV-positive man known as the Berlin patient, who received a bone marrow transplant in 2007 to treat his leukemia. The bone marrow donor was one of the rare individuals with two copies of a variant of the CCR5 gene that does not allow HIV to enter T-cells. After his transplant, the Berlin patient’s HIV counts dropped to undetectable levels, and he was able to stop taking antiretroviral drugs. Using bone marrow transplants as treatments for HIV wouldn’t be practical for many people, because the donor would not only need to have two mutant CCR5 gene copies, but would also have to be immunologically compatible with the recipient. But because it uses a patient’s own cells, a gene therapy could theoretically be used on anyone.
Sangamo’s anti-HIV program in hematopoietic stem cells is supported by a 2009 grant by California’s stem cell research funding agency, the California Institute for Regenerative Medicine. The agency is also providing funds for Calimmune’s recently launched early stage trial. Calimmune’s HIV treatment, called Cal-1, modifies both the patient’s T-cells and their hematopoietic stem cells in an attempt to block more avenues for the HIV virus to invade.
While Sangamo uses zinc finger proteins to modify genes, Calimmune relies on a form of RNA interference to essentially turn off the production of the CCR5 protein, even though the gene itself remains intact. The technique is based on work from the lab of Nobel laureate David Baltimore, chairman of Calimmune’s board of directors. The company expects to report results of the trial in 2015.
Sangamo, in another project recently funded by the California Institute for Regenerative Medicine, is attempting to cure beta-thalassemia, a blood disease that keeps patients dependent on blood transfusions for survival. In this disorder, a faulty gene produces a defective form of hemoglobin, the protein in red blood cells that transports oxygen through the body.
Lanphier says Sangamo could use a number of different tactics in beta-thalassemia. For example, it could insert a normal gene for hemoglobin into hematopoietic stem cells. Or, it could modify the stem cells to switch on a gene for a fetal form of hemoglobin that usually turns off as the patient gets older. Either way, the genetically modified stem cells might liberate patients from lifelong treatment.
“They would no longer need blood transfusions,” Lanphier says.
Sangamo’s platform is not limited to modifying the genes in blood cells after they have been extracted from the body. In late 2012, the company outlined a new method called In Vivo Protein Replacement that is being developed in pre-clinical studies. In this approach, a DNA-editing-enzyme-based is delivered systemically into the body itself, where it inserts a missing gene into liver cells. In mice, Sangamo was able to produce human Factor IX, a clotting factor that is missing or scant in people with hemophilia B, increasing their risk of bleeding.
This in vivo gene therapy method could be used in other diseases caused by the absence of a single gene, Sangamo says. Such conditions include Fabry disease, in which a single missing enzyme, alpha-galactosidase A, can lead to kidney failure and other severe consequences. Fabry disease can now be treated with periodic infusions of a replacement protein called agalsidase beta, (Fabrazyme), marketed by Sanofi/Genzyme. But like the antiretrovirals used to treat HIV infections, enzyme replacement therapies can cause significant side effects.
Sangamo plans to ask the FDA for permission to start clinical trials for seven new treatments by 2015. Lanphier sees the zinc finger platform as a disruptive technology that could eliminate the need for maintenance treatments such as HIV drugs.
“What we’re trying to do is permanently change the DNA in the patient,” Lanphier says. “Therefore, they no longer have the disease.”
