Final Activity Report Summary - HUNTER (Screening for peptides that revert mutant huntingtin induced abnormal phenotypes)
Huntington's disease (HD) is an inherited neurodegenerative disorder that usually begins in midlife and affects approximately 1 in 10 000 individuals. HD patients demonstrate severe neurological symptoms that gradually worsen with age. After 10 to 15 years from the disease onset patients lose their intellectual abilities and must rely on total care for their activities. Death usually occurs from asphyxia or heart attack and there is currently no cure for the disease.
The gene responsible for the disease was identified in the early nineties and, since then, many progresses were made in understanding the molecular and cellular disease basis. The HD gene product, named huntingtin, has a protective role in neurons, but, when mutated, acquires toxic properties leading to neurodegeneration.
Several therapeutics strategies have been proposed, including administration of anti-oxidant molecules, replacement therapy with stem cells and delivery of growth factors in the brain. Mutant huntingtin itself is; however, a validated drug target. A reasonable therapeutic approach consists of identifying molecules that inhibit toxic activities of mutant huntingtin or its abnormal protein interaction.
In this project we isolated small peptide aptamers that bound mutant huntingtin under the hypothesis that their binding might interrupt pathological interactions in the cell. These peptides were then tested for their ability to rescue various pathological phenotypes using cell culture and mice models of the disease available in our laboratory.
The novelty of our approach relied on the possibility to directly target the trigger mechanism of the disease and not the late consequences of the pathogenic insult. The peptides we isolated were under study, by the time of the project completion, for the design of small molecules to be used for a therapeutic intervention of this incurable disease. This research presented a potential high content in intellectual property. Finally, the validated peptide sequences were to be patented as part of the project.
The gene responsible for the disease was identified in the early nineties and, since then, many progresses were made in understanding the molecular and cellular disease basis. The HD gene product, named huntingtin, has a protective role in neurons, but, when mutated, acquires toxic properties leading to neurodegeneration.
Several therapeutics strategies have been proposed, including administration of anti-oxidant molecules, replacement therapy with stem cells and delivery of growth factors in the brain. Mutant huntingtin itself is; however, a validated drug target. A reasonable therapeutic approach consists of identifying molecules that inhibit toxic activities of mutant huntingtin or its abnormal protein interaction.
In this project we isolated small peptide aptamers that bound mutant huntingtin under the hypothesis that their binding might interrupt pathological interactions in the cell. These peptides were then tested for their ability to rescue various pathological phenotypes using cell culture and mice models of the disease available in our laboratory.
The novelty of our approach relied on the possibility to directly target the trigger mechanism of the disease and not the late consequences of the pathogenic insult. The peptides we isolated were under study, by the time of the project completion, for the design of small molecules to be used for a therapeutic intervention of this incurable disease. This research presented a potential high content in intellectual property. Finally, the validated peptide sequences were to be patented as part of the project.