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SORT1:PGRN blocking antibodies for Frontotemporal dementia

SORT1：针对额颞叶痴呆的 PGRN 阻断抗体

基本信息

批准号：
9322703
负责人：
Arnon Rosenthal
金额：
$ 129.42万
依托单位：
ALECTOR, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9322703
关键词：
Acute Affect Affinity Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model American Antibodies Antibody Formation Behavior Behavioral Binding Blocking Antibodies Caring Cell surface Cells Cellular Assay Characteristics Chronic Clinic Clinical Cognition Conditioned Culture Media Data Set Dementia Development Diagnosis Disease Disease Progression Disease model Drug Exposure Drug Kinetics Emotional Endocytosis Frontotemporal Dementia Funding Generations Goals Health Human Hybridomas In Vitro Language Late Onset Alzheimer Disease Lead Life Measures Medical Memory impairment Monoclonal Antibodies Motor Movement Mus Mutation Nerve Degeneration Neurodegenerative Disorders PGRN gene Patients Pharmacodynamics Phase Plasma Preclinical Testing Presenile Dementia Production Progressive Disease Property Proteins Public Health Risk Factors Secure Signal Transduction Surface Plasmon Resonance Symptoms Technology Testing Therapeutic Therapeutic antibodies Yeasts behavioral impairment cognitive performance effective therapy extracellular improved in vitro Assay in vivo nervous system disorder neuroinflammation neurotrophic factor novel receptor sortilin stable cell line tau Proteins

项目摘要

DESCRIPTION (provided by applicant): SORT1 blocking antibodies for Alzheimer's disease and Frontotemporal dementia Alector's objective is to develop therapeutic antibodies against the receptor Sortilin1 (SORT1) for the treatment of the devastating neurological disorders Frontotemporal Dementia (FTD) and Alzheimer'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 ~50,000-60,000 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 5M 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 3-4 years after symptom onset, with a median survival of 6-11 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 10% of all FTD cases, while other alleles are associated with the development of late onset AD. SORT1 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 SORT1, 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 SORT1 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 SORT1 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.

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（8）

Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia.

Latozinemab，一种治疗额颞叶痴呆的新型颗粒体蛋白前体升高疗法。

DOI：
10.1186/s12967-023-04251-y
发表时间：
2023-06-15
期刊：
JOURNAL OF TRANSLATIONAL MEDICINE
影响因子：
7.4
作者：
Kurnellas, Michael;Mitra, Ananya;Schwabe, Tina;Paul, Robert;Arrant, Andrew E.;Roberson, Erik D.;Ward, Michael;Yeh, Felix;Long, Hua;Rosenthal, Arnon
通讯作者：
Rosenthal, Arnon