SORT1:PGRN blocking antibodies for Frontotemporal dementia

 描述(申请人提供)：针对阿尔茨海默病和额颞叶痴呆的SORT1阻断抗体Alector的目标是开发针对Sortilin1受体(SORT1)的治疗性抗体，用于治疗毁灭性的神经疾病额颞叶痴呆(FTD)和阿尔茨海默病(AD)。FTD是一种进行性疾病，会导致行为、语言、运动和认知的丧失能力变化，是最常见的老年前期痴呆，在美国影响约50,000-60,000人。AD是痴呆最常见的病因，它与FTD有许多共同的病理和表型特征。据估计，美国有500万人患有阿尔茨海默病，而且人数还在稳步增加，这是一个重大的公共卫生问题。对于FTD没有有效的治疗方法，FTD通常在症状出现3-4年后被诊断出来，中位生存期为6-11年。此外，目前还没有可用的治疗方法来阻止AD的进展。最终，患有FTD或AD的患者将需要全天候的医疗护理。前颗粒蛋白(PGRN)是一种神经营养素，已被确定为神经退行性疾病的危险因素。在所有FTD病例中，有10%是由PGRN单倍体不足引起的，而其他等位基因与晚发性AD的发生有关。SORT1是一种跨膜受体，通过与细胞表面结合并迅速将其内化以降解溶酶体来控制PGRN的胞外水平，而它对PGRN信号转导是必不可少的。我们建议通过开发结合SORT1的抗体来提高PGRN的细胞外水平，阻断与PGRN的相互作用，从而在体外和体内从功能上提高PGRN的水平。有效的铅抗体将在亲和力和其他特性方面进行优化，并作为开发候选者进行验证性和临床前测试。在这个项目中产生的数据集和SORT1抗体都将使我们能够获得必要的额外资金，以推动候选人进入临床前测试、IND提交和临床。针对PGRN突变患者的SORT1抗体试验将最终确定治疗性PGRN升高是否如假设的那样在FTD和AD患者中提供有意义的临床益处。

 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.