Gene therapies still may be years away from the market, but whenthey get there Ariad Pharmaceuticals Inc. plans to have themechanism ready to counter any ill effects from tinkering with thebody's DNA make-up.
In fact, gene and cell therapies may never pass muster with patients,doctors or the FDA without being fitted with a molecular fail-safesystem.
"It's an accepted axiom in the industry that the FDA looks fortherapies that are reversible," said Charles Cabot, chief operationsofficer of Cambridge, Mass.-based Ariad. "There hasn't been anadequate means to reverse gene therapy."
To develop one, Ariad purchased from Osaka Bioscience Institute, inJapan, the FAS gene, which expresses an intracellular proteininvolved in programmed cell death, also called apoptosis. The licensegives Ariad worldwide rights to FAS for gene and cell therapy.Financial terms were not disclosed.
Ariad's plan is to deliver along with a therapeutic gene a cassette ofgenetic material encoding a portion of the FAS receptor combinedwith a drug binding domain. Wherever the therapeutic gene goes, theFAS gene cassette would settle into the cell's DNA and expressmultiple copies of the FAS receptor-drug binding domain complex.
If the intended gene therapy generated adverse side effects oraccomplished its task and was no longer needed, the patient wouldswallow a small molecule drug developed by Ariad to dimerize, orbring together, the FAS receptors, activating the pathway that leads tocell death. The intended result would be to eliminate geneticallyengineered cells from the patient.
Cabot said the FAS system, which is expected to enter clinical trialsnext year, can be used with any type of gene or cell therapy, ex vivoand in vivo. And it could be applied not only as a fail-safemechanism, but also to control groups of engineered cells to boosttheir effectiveness.
The principle behind the FAS system is the same as that employed byAriad in developing a method for regulating expression in vivo oftherapeutic genes delivered in gene therapy. (See BioWorld Today,Aug. 29, 1996, p. 1.)
Cabot said the initial clinical trials next year will assess the safety ofa dimerizing drug and the application of a FAS system with adoptiveimmunotherapy in cancer patients.
The immunotherapy, which still is in clinical development, involvestaking peripheral blood cells (subsets of white blood cells),expanding their number, and injecting them in patients to launch animmune system attack on the cancer.
A potential side effect of "charging up" the immune system, Cabotnoted, is graft-vs.-host disease in which the killer cells assault non-cancerous tissues.
To offset that danger, Ariad's FAS gene cassette would be introducedex vivo to the peripheral blood cells as they are grown for theimmunotherapy. The therapeutic cells then would be administered tothe cancer patient armed with a fail-safe mechanism.
Before the clinical trials of the FAS system can begin, Ariad willhave to negotiate an alliance with a company developing the adoptiveimmunotherapy. Cabot said Ariad is talking with several firms.
Ariad's stock (NASDAQ:ARIA) closed Thursday at $4, up $0.032. n
-- Charles Craig
(c) 1997 American Health Consultants. All rights reserved.