The Foster City, CA-based biopharmaceutical giant Gilead (NASDAQ: GILD) reaps about $8 billion a year from its daily drug regimens that keep the HIV virus in check. Gilead’s Bay area neighbor, San Rafael, CA-based BioMarin Pharmaceutical (NASDAQ: BMRN), earns nearly half a billion dollars annually from its pioneering drugs for rare disorders that would otherwise cripple or kill children. Despite those significant advances in medicine, rising companies such as Richmond, CA-based Sangamo BioSciences (NASDAQ: SGMO) think they can do much better. They’re trying to free patients from a lifetime of pills or infusions by giving them one-time doses of gene therapy.
Gene therapy—a treatment based on modifying or correcting human genes and introducing them into the body—is a fast-growing research area. The treatments are often designed to inactivate a gene that causes a disease, or replace an essential gene that is missing. Although the FDA has not yet approved a gene therapy, the European Commission in November 2012 approved alipogene tiparvovec (Glybera) as a genetic remedy for a very rare defect in fat metabolism caused by the lack of an enzyme called lipoprotein lipase. The treatment inserts a gene that codes for the enzyme. Its developer, uniQure of Amsterdam, the Netherlands, announced Tuesday it has signed a commercialization agreement for the treatment with Parma, Italy-based Chiesi Farmaceutici.
Back in 1999, the promise of gene therapy took a body blow when 18-year-old Jesse Gelsinger died as a result of an early attempt to correct a rare disorder with introduced genes. But lately, the field has escalated into a race among researchers trying gene therapies for everything from eye ailments to blood disorders. Sangamo is conducting clinical and preclinical studies of gene-based therapies for HIV infection, among other diseases. A rival, Los Angeles, CA-based Calimmune, announced Tuesday it had treated the first patient in a trial of its own gene-based HIV remedy, with an approach that shares some features with Sangamo’s.
Sangamo is using its proprietary gene-editing technology to disable a gene, CCR5, which helps the HIV virus invade key immune system cells called T-cells. In its ongoing clinical trials, the company isolates T-cells from a patient’s blood, knocks out the troublesome gene, and then returns the cells to the body where they can better fight off HIV. The hope is that the modified T-cells will multiply and pass along their strengthened genetic blueprint to their progeny, giving a patient long-lasting protection from the viral infection that can lead to AIDS if untreated.
In an alternate strategy, Sangamo is applying the same CCR5 gene-editing technique to the hematopoietic stem cells that circulate in the blood and give rise to blood and immune system cells. The modified stem cells may provide a more enduring source of T-cells protected from HIV infection compared with treating the T-cells themselves.
“There are reasons to do both approaches, so that’s what we’re doing,” says Sangamo CEO Edward Lanphier.
Sangamo has developed a mix-and-match technology platform that has allowed the company to tackle a range of diseases with the experimental strategy, or strategies, that seem to have the best shot at success in each indication. The company, which is less than an hour’s drive from both Gilead and BioMarin, is exploring the use of its gene therapy methods against HIV and mucopolysaccharidosis I, one of the debilitating disorders addressed by BioMarin’s enzyme replacement therapies. In a partnership with Shire of Dublin, Ireland, Sangamo is also researching potential treatments for hemophilia A, hemophilia B, and Huntington’s disease.
The core of Sangamo’s platform is a stable of compounds called zinc finger proteins, which can be tailored to home in on a specific gene associated with a particular disease. The proteins are made up of single units that each bind to certain three-letter sequences of DNA. When two or more zinc finger units are assembled into a sort of “hand,” the zinc finger protein can selectively grab the exact section of a gene that Sangamo wants to target.
These gene grippers can then be connected to a number of other molecular tools, such as a protein that silences the target gene, or a set of enzymes called nucleases that clip the problematic gene out of the DNA strand in a chromosome. These nucleases can also help insert a replacement gene.
In its preclinical program in Huntington’s disease, Sangamo is using the first tool combination: a zinc finger protein connected to a transcription factor that curbs the expression of the mutant form of the Huntingtin gene, which causes progressive nerve damage and eventual death in afflicted patients. For patients with a second copy of the gene that is normal (which is typically the case), this treatment allows that normal copy to function properly.
To protect T-cells from HIV invasion, however, Sangamo uses the second combination of tools: zinc finger proteins) connected to DNA-clipping nuclease enzymes. The enzymes attach at either end of the CCR5 gene and snip it out. Sangamo’s ultimate goal is to 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.”
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