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Tomorrow's Drugs
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Pharmaceutical Executive


Genetic editing just might grant great wishes in the treatment of modern disease

Think of it as the ultimate step in moving treatment upstream: reprogramming the genome itself. The evolving field known as genetic editing is showing promise as the future means of treating cancer, sickle-cell anemia, and certain forms of immune-deficiency disease.

At the heart of the process are molecules called zinc finger DNA-binding proteins (ZFPs). These naturally occurring proteins are transcription factors; that is, they regulate how DNA behaves. And the ZPFs can be engineered to perform different functions.

"Different functional domains can be attached to the ZFP to create proteins with different functions," said Elizabeth Wolffe, PhD, spokeswoman for California-based Sangamo BioSciences. "One can add a transcriptional activator or repressor domain to make a ZFP transcription factor [ZFP TF] that can be used to regulate a gene's expression up or down; or one can attach a nuclease domain to make a ZFP nuclease [ZNF] that can cut DNA at a specified site in the genome. We then use the cell's natural DNA-repair mechanism to drive a process of disruption, correction, or DNA addition, depending on what we want to do."

"The advantage in gene editing is that you're relying on the native machinery of the cell, with no enhancers," said Elazar Rabbani, founder and chairman of New York–based Enzo Biochem, which holds several patents in gene editing. "Once the gene has been successfully edited, it lasts for the lifetime of the cell."

The earliest uses of gene editing will probably treat cells outside the body. "Our initial therapeutic applications of our ZFN technology are focused on diseases of blood and the immune system," says Wolffe. "For example, HIV—in which we are disrupting the CCR5 receptor in T cells. In this application, cells will be removed from the patient, modified ex vivo using our ZFNs, expanded and qualified, and returned to the body."

Sangamo expects to initiate a Phase I trial of the process this year. Based on earlier studies by other groups, Wolffe estimates that treatment can make T cells permanently resistant to HIV for the life of the cells—a year to 18 months. "We have shown that the T cells have a selective survival advantage in the presence of HIV," she says. "One other important note is that the ZFNs only need to be present in the cell transiently to have a permanent effect. We have also demonstrated that these ZFNs can be used in stem cells and, thus, would be expected to have a far longer-term effect, as all the progeny of these stem cells would be modified."

Coming up behind the HIV treatment in Sangamo's pipeline is a therapy for glioblastoma, a brain cancer. Here, the strategy is to disrupt the glucocorticoid receptor in T cells that can kill glioblastoma cancer cells. The engineered cells—not the patient's own—will be injected into the brain in the presence of glucocorticoids to suppress rejection.

Genetic editing won't be cheap. But Rabbani stands by the technology. "I wouldn't call it expensive," he said. "Especially when the progeny of the cell can go on forever. I believe that whole-gene manipulation actually is one of the most promising approaches for people with genetic diseases like cancer." –CAROLYNNE VAN HOUTEN


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