SORT1:PGRN blocking antibodies for Frontotemporal dementia

DESCRIPTION provided by applicant SORT blocking antibodies for Alzheimerandapos s disease and Frontotemporal dementia Alectorandapos s objective is to develop therapeutic antibodies against the receptor Sortilin SORT for the treatment of the devastating neurological disorders Frontotemporal Dementia FTD and Alzheimerandapos s Disease AD FTD is a progressive disease that causes incapacitating changes in behavior language movement and cognition and is the most common of the pre senile dementias affecting people in the US AD is the most common cause of dementia which shares many pathological and phenotypic features with FTD As AD affects an estimated M Americans with the numbers increasing steadily the disease represents a major public health issue There is no effective treatment for FTD which is typically diagnosed years after symptom onset with a median survival of years Furthermore there are no available treatments that halt progression of AD Ultimately patients with FTD or AD will require round the clock medical care Progranulin PGRN is a neurotrophin that has been identified as a risk factor for neurodegenerative diseases PGRN haploinsufficiency is causal for of all FTD cases while other alleles are associated with the development of late onset AD SORT is a transmembrane receptor that controls the extracellular level of PGRN by binding it at the cell surface and rapidly internalizing it for lysosomal degradation while it is dispensable for PGRN signaling We propose to generate a therapeutic that can elevate extracellular levels of PGRN by developing antibodies that bind SORT block the interaction with PGRN and thus functionally elevate PGRN levels in vitro and in vivo Effective lead antibodies will be optimized for affinity and other characteristics and advanced for confirmatory and preclinical testing as development candidates Both the dataset and SORT antibodies produced in this project would allow us to secure the additional funds necessary for advancing the candidate to preclinical testing to IND submission and to the clinic Trials with a SORT antibody in patients with PGRN mutations would conclusively determine whether therapeutic PGRN elevation could provide meaningful clinical benefit in FTD and AD patients as hypothesized PUBLIC HEALTH RELEVANCE The goal of the present project is the development of a therapeutic Sortilin antibody that would increase the levels of Progranulin PRGN whose deficiency is causal to Frontotemporal Dementia FTD and is a risk factor for Alzheimerandapos s disease AD FTD is a devastating progressive neurodegenerative disorder that causes debilitating behavioral and emotional changes and it is the most common cause of pre senile dementia AD is a disease of aging that is the most common cause of dementia afflicting more than M Americans with progressively incapacitating memory and behavioral impairments There are currently no treatments for FTD no treatments that arrest AD progression and no proven treatments that can therapeutically elevate PRGN in haploinsufficient subjects