Yale Researcher Succeeds in Creating Blood Vessels using Artificial Means

A Yale researcher and collaborators have succeeded in creating an artificial transcription factor, which is the light switch that turns genes on and off, and induced the growth of new blood vessels in a live laboratory mouse, it was reported in the journal Nature Medicine.

“This is the first time that we have been able to design and use an artificial transcription factor to regulate a gene in any animal,” said the senior author of the study, Frank Giordano, M.D., assistant professor of medicine, and director of the Yale Vector Core of the Yale Cancer Center and director of the Cardiovascular Gene Therapy Program. The journal article was made available online this month and is scheduled for publication in December.

Giordano said that the same approach could work in humans, but that this will await completion of ongoing research and toxicology studies to insure patient safety.

“This approach represents a new paradigm in gene therapy that is predicated on the modulated expression of endogenous genes,” the researchers said in the study. “There are considerable potential advantages to this approach, including the ability to regulate all the natural splice variants of an endogenous gene with a single deliverable effector molecule.”

The zinc finger protein (ZFP) transcription factor used in the study was designed by Sangamo BioSciences of Richmond, Calif., and several of the company’s scientists are co-authors of the study. The ZFP is one of four common structural themes for protein structures that bind to DNA and generate cell production.

In the study reported in Nature Medicine, Giordano constructed and used viral vectors to introduce the artificial transcription factors into laboratory mice and induced the growth of new blood vessels in the animals’ ears. The procedure also promoted healing of wounds.

The researchers said that, based on the results, there appeared to be several advantages to use of an artificial transcription factor when compared to conventional gene therapy, where patients are injected with DNA encoding a single gene product in hopes of stimulating growth. The new blood vessels in the study appeared to be more mature than those induced by standard gene therapy.

“Complex processes such as blood vessel growth and wound healing involve multiple genes and splice variants,” Giordano said. “Using the ZFP approach, multiple separate genes can be regulated with a single therapeutic intervention.”

“ZFP-based transcription factors can be designed to activate, or, when combined with a repression domain, to repress expression of nearly any endogenous gene,” Giordano said. “The inherent generality and versatility of this approach has notable implications for gene-based therapies predicated on the regulation of complex biological processes such as angiogenesis (growth of new blood vessels). These studies establish, for the first time, the feasability and potential utility of this approach in vivo.”

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