Making good on its promise to unveil a third drug-development program in the first half of 2005, Benitec said last week that it intends to begin work on an RNAi-based treatment for diabetes, obesity, and related disorders.
Benitec said it signed a licensing deal with Australia’s Garvan Institute of Medical Research to acquire intellectual property related to the c-Cbl gene, which encodes for a protein that plays a role in regulating receptor tyrosine kinase signaling. Absence of the gene in mice, Benitec said, has been associated with type II diabetes resistance, as well as increased fat burning and muscle building.
The c-Cbl IP is based on the work of Garvan Institute senior scientist David James, Benitec said. In the Journal of Clinical Investigation late last year, James and colleagues published a paper finding that c-Cbl-deficient mice, while eating the equivalent of an extra meal a day, “maintained about a half of the normal complement of body fat,” he told RNAi News this week. The mice were also more active and displayed a significant improvement in whole-body insulin action.
“We’re not 100 percent sure [of the reasons behind this], but one of the things that’s clearly happening is that the muscle in these animals is burning fat,” he said. The mice “eat, the nutrients come in and top up their essential food reservoirs, and the excess just gets burned in muscle.”
The mice “are hungry because they perceive they’re not getting enough fuel, so they eat more,” James added.
James said that this work indicates the existence of a regulatory pathway responsible for deciding whether nutrients are going to be either stored up or burned. Next up, then, is to do “a little bit of interrogation to figure out the mechanism [of action], because we don’t know 100 percent where the loss of c-Cbl is required in order to derive [a] beneficial effect,” he said.
This work is expected to be done with Benitec, which also said that it has entered talks with the Garvan Institute to form a research collaboration focused on developing RNAi-based drugs targeting c-Cbl.
James sees the gene as a good target for RNAi since new data coming from his lab indicates that “heterozygous knockout [mice] have a phenotype that’s sort of somewhere in between. That means that you don’t have to knock the whole thing out completely to get benefit,” he said.
“I think as far as RNAi goes that’s really important because we’re seeing so many examples in RNAi where in order to see any phenotype at all, you have to almost completely ablate the expression of your [target] gene,” he added.
James concedes that a big question facing the development of a drug that targets c-Cbl is the fact that it is a proto-oncogene. “Do we really want to be making drugs that might turn on a proto-oncogene? The answer to that [is that while] we haven’t done a large-scale experiment … but we certainly have had animals down in the animal house for several years — that’s close to the lifespan of a mouse — [and they] don’t seem to exhibit any evidence for increased tumerogenesis.”
Benitec’s announcement about the deal comes less than a week after the company’s acting-CEO Sara Cunningham — who was appointed following the abrupt resignation of former Chairman and CEO John McKinley — said during a conference call that “a third development program, which will broaden [the company’s] pipeline without significantly losing focus,” would be announced shortly (see RNAi News, 2/4/2005). Benitec is currently developing an HIV therapy in collaboration with the City of Hope and a hepatitis C treatment in house.
“The Garvan license further strengthens our pipeline, focusing primarily on clinical indications for which RNAi therapeutics are uniquely suited,” Cunningham said in a statement. “Infectious diseases such as HIV and HCV, and disorders involving multiple genes such as obesity and diabetes, are more readily addressed by the multi-target capability of RNAi.”