Re-engineering progranulin as an Alzheimer’s and FTD disease-modifying therapeutic
McGill University Health Centre/Centre universitaire de sante McGill
Progranulin is a protein with important roles in the brain. Mutation of progranulin results in a disease called frontotemporal dementia in which parts of the brain, responsible for planning, judgement, emotion, and speech, slowly decay. Increasing progranulin levels in animal models of Alzheimer’s disease prevents the onset of disease symptoms. Developing effective methods to deliver progranulin to the brain are therefore likely to have beneficial effects in the treatment of Alzheimer’s disease and other dementias. The cells of the brain are separated from the general blood stream by the blood-brain barrier. This allows critical nutrients to pass into the brain but prevents toxins or drugs from entering. To use progranulin as a therapy for Alzheimer’s disease and other dementias we need to develop ways to get it to pass across the blood-brain barrier. One way to do this is to link progranulin to sepecial antibodies that are known to cross the blood brain barrier and which will carry progranulin into the brain. We will, therefore, first design and construct combinations of progranulin with these antibodies, then test their ability to cross the blood-brain barrier and finally test their ability to treat Alzheimer’s-like disease in mice.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Progranulin has protective activity to slow or even stop the development of diseases such as Alzheimer’s disease and frontotemporal dementia in experimental models. There is, however, no means to deliver progranulin to the brain in patients. This is largely because the blood-brain barrier blocks the passage of progranulin from the blood to the brain. By developing combination proteins where progranulin is linked to a carrier antibody that is known to cross the blood-brain barrier we will be able to deliver progranulin to the brain with much higher efficiency than is now possible and therefore accelerate development of progranulin-based brain therapies.
At the completion of this project we expect to have developed and optimize progranulin-antibody combination proteins, established the parameters governing their transport across the blood-brain barrier and determined their ability to modify the development of Alzheimer’s-like symptoms in an Alzheimer’s disease mouse model. Success in this project will then allow us to move the project forward towards delivery of progranulin into patient brains to treat Alzheimer’s disease and other neurodegenerative diseases of aging.