Circadian to fund new antisense Alzheimer's project

Melbourne biomedical company Circadian Technologies (ASX: CIR) has announced it will fund a project at Melbourne University to develop an antisense therapy for Alzheimer's disease.

Circadian's executive director, Graeme Kaufman, said the therapy would be aimed at deleting a receptor from neurons that triggered programmed cell death, or apoptosis.

Research into Alzheimer's disease and related brain disorders like Parkinson's disease and motor neuron disease have implicated apoptosis in the mass death of neurons in vital areas of the brain.

In Alzheimer's disease, there is massive loss of cholinergic neurons from the frontal lobes, where higher cognitive functions are centred, and the hippocampus, which coordinates the formation of long-and short-term memories.

Cholinergic neurons produce the neurotransmitter acetylcholine, which has a key role in thought processes and memory -- as ACH levels fall, memory and higher thought processes fade.

Current drugs for Alzheimer's disease seek to boost ACH production, but have little effect in slowing the progression of the disease -- and they become less effective as the disease progressively kills more neurons.

Circadian and other companies are trying to develop new therapies to keep injured cholinergic neurons alive and active in aging brains.

In the late 1990s, Dr Graham Barrett of the Water and Eliza Hall Medical Research Institute (WEHI) in Melbourne's Parkville, identified the receptor for a signalling molecule called P75 as a key player in the loss of cholinergic neurons -- P75 is one of a class of molecules called apoptosis factors.

P75 receptors are localised to cholinergic neurons in the frontal lobes and hippocampus, making them an ideal target for a novel Alzheimer's therapy, according to Kaufman.

Barrett's team showed, in an animal model, that inhibiting the P75 receptor decreased the loss of aging cholinergic neurons, as well as increasing their size and output of ACH. Other research overseas on animal models has confirmed that the P75 receptor has a key role in transmitting the P75 gene's suicide signal.

Circadian, through its wholly-owned subsidiary, Polychip Pharmaceuticals, acquired the intellectual rights to the WEHI discovery.

Circadian announced today it has allocated $440,000 over the next three years for Barrett, now at Melbourne University, to develop a new therapy and delivery system. As with any molecule targeted to the brain, the challenge is to spirit it through the highly impermeable blood-brain barrier.

Kaufman said the project will try to develop an antisense RNA molecule to switch off the P75 receptor gene.

Once inside the brain, the RNA molecule should be readily taken up by neurons. It will bind to and inactivate the messenger RNA 'recipe' from the P75 receptor gene, transiently deleting the molecule from the surface of cholinergic neurons, preventing them from responding to P75's suicide instruction.

Kaufman said the therapy, if successful, would probably need to be repeated at monthly intervals, because the antisense molecules had a limited lifespan in the brain.

But he said the inhibitor approach was potentially more effective than that in currently available Alzheimer's drugs.