TORONTO _ Increased understanding of molecular diseasemechanisms has led to increased optimism that new rationaltherapeutic approaches could be developed to interfere with diseasemechanisms at a much earlier stage in apoptosis, or cell death. Thisearlier intervention may be more effective than strategies that try torepair the damage caused by apoptosis since it could prevent neuronsfrom injury.
The latest example of this type of approach comes from novelresearch being conducted by scientists at the Center for MolecularMedicine and Therapeutics (CMMT), in Vancouver, and MerckFrosst Canada Inc., of Montreal. Their discoveries could pave theway for the development of therapeutic treatments for patientssuffering from Huntington's disease (HD).
Paul Goldberg and Michael Hayden, at the CMMT, in conjunctionwith Donald Nicholson, at the Merck Frosst Center for TherapeuticResearch in Montreal, have reported in the Aug. 1, 1996, NatureGenetics, that Huntingtin, the protein product produced by the HDgene, is directly involved in a particular apoptosis pathway that leadsto death of brain cells. In addition, their research indicates that thegenetic mutation causing HD directly influences how Huntingtinparticipates in the apoptosis pathway.
The mechanism leads to damage of the nerve cells in various areas ofthe brain including the basal ganglia and cerebral cortex.
HD is caused by a faulty gene on chromosome 4. It is an inheriteddisease with symptoms resulting from brain damage, includinggradual physical, mental and emotional impairments. Typically, thesesymptoms first appear in the prime of a person's life between 35 and45 years of age, progressing without any relief to deathapproximately 15 years from the time of onset.
There is no cure for HD and treatment has been limited to alleviatingthe symptoms that manifest themselves during the course of thedisease such as deterioration of control of movement and variouspsychological conditions including depression, anxiety andpsychosis.
According to Hayden, who is director of the CMMT and professor ofmedical genetics at the University of British Columbia, their mostrecent research has demonstrated that Huntingtin can be cleaved bycysteine proteases.
Cell death only occurs, the researchers discovered, when thepolyglutamine encoding CAG repeat in the gene expands. Thus, ifthis process could be controlled then the development of the diseasecould be prevented. This is exactly what the researchers found. Therate of cleavage of Huntingtin increases with the length of theHuntingtin polyglutamine tract.
The researchers used apopain, which plays a key role in proteolyticevents leading to apoptosis, and is a human counterpart of thenematode cysteine protease death-gene product, CED-3.
Hayden said that, "These findings offer a new rational basis fordeveloping treatment strategies for people at risk for HD. For the firsttime, therapeutic agents, based on cysteine proteases, can be designedto limit or perhaps prevent this disease in the long term by preventingbrain cell death."
Although the researchers has successfully demonstrated in thelaboratory that cysteine proteases, developed at Merck Frosst, caninterfere with the cell death pathway in HD, Hayden said theexperimentation now has to be broadened to animal studies.
The group at the CMMT already has succeeded in cloning the genefor the mouse version of HD. This animal model now will be used toexamine if the inhibitors perform as well in this situation.
The CMMT is a recent research initiative involving the University ofBritish Columbia, the British Columbia Children's Hospital and aC$15 million operating grant from Merck Frosst Canada Inc. n
-- Peter Winter Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.