The Foster City, CA-based biopharmaceutical giant Gilead (NASDAQ: [[ticker: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: [[ticker: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: [[ticker: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
