Gene Therapy Center helps solve longstanding biological mystery

A recent paper in the journal Nature outlines an important scientific discovery facilitated by UAB Gene Therapy Center (GTC) gene transfer technology (2006;443:993-997). “Gene transfer tools have utility that goes beyond therapy,” explains GTC Director David T. Curiel, MD, PhD, a paper coauthor. “This research is one example of how gene therapy can help answer longstanding, complex, biological questions.”

The paper outlines the molecular basis of corneal avascularity, a puzzle that had confounded scientists for many years. Despite being surrounded by highly vascularized tissue and containing vascular endothelial growth factor (VEGF) — a potent promotor of angiogenesis — the cornea stays clear of blood vessels. This unique situation enables optimal sight and also makes corneal tissue an ideal platform for testing strategies that promote or inhibit blood vessel growth.

Authors of the Nature paper identified the molecular “handcuff” that keeps VEGF in check in corneal tissue. The researchers hypothesized that soluble VEGF receptor-1 (sflt-1) is the key to corneal avascularity.

Using a GTC-designed adenovirus that expresses sflt-1, investigators showed inhibiting this molecule unlocks the handcuff and causes blood vessels to form in corneal tissue. Investigators also used genomic deletion and RNA interference to validate their theory. All three strategies confirmed sflt-1 is responsible for inhibiting VEGF and preventing angiogenesis.

Transient Transgenic Animals
Researchers studying corneal avascularity also capitalized on a UAB GTC-developed approach that selectively perturbs phenotypes in experimental animals. GTC scientists had previously put forth a transient transgenic mouse model, in which the phenotype of an adult animal is altered to provide transient expression of tumor antigens. This model overcomes several limitations of conventional transgenic mice, including the challenges and expense involved in establishing transgenic strains for in vivo analysis of targeted therapies.

“Investigators sought to perturb this highly selective antiangiogenesis arc in the cornea and used both our gene transfer tools and transient transgenic approach, which avoids the complexity and biological ambiguity of transgenic mouse models,” Curiel says. “Their findings validate that our virus-encoding molecule is a powerful antiangiogenesis agent and supports its advancement as an antitumor therapy.”

Understanding angiogenesis and the switch that turns the process off or on can potentially enhance treatment for a number of human diseases, including diabetes, cancer, and atherosclerosis, Curiel says.

“Research now shows that cancer gene therapies can be effective even in the most refractory cases of disease [gene therapy recently produced full clinical regression in two patients with advanced melanoma] and that gene transfer technology is an increasingly useful tool for dissecting complicated biological questions,” he says. “In the postgenome era, research is focused on ‘gene on/gene off’ studies that allow ascription of protein function. Gene transfer is a critical technology that allows scientists to turn these genes off and on and reveal answers to longstanding questions about human health and disease.”

For more information:
Dr. David Curiel
1.800.UAB.MIST
mist@uabmc.edu