SORT1:PGRN blocking antibodies for Frontotemporal dementia

 描述（由申请人提供）：用于阿尔茨海默病和额颞叶痴呆的SORT 1阻断抗体Alector的目的是开发针对受体Sortilin 1（SORT 1）的治疗性抗体，用于治疗破坏性神经障碍额颞叶痴呆（FTD）和阿尔茨海默病（AD）。FTD是一种进行性疾病，可导致行为、语言、运动和认知的失能性变化，是最常见的老年前期痴呆，在美国约有50，000 - 60，000人受累。AD是痴呆的最常见原因，与FTD具有许多共同的病理和表型特征。据估计，AD影响着500万美国人，随着人数的稳步增加，这种疾病代表了一个主要的公共卫生问题。FTD没有有效的治疗方法，通常在症状发作后3-4年诊断，中位生存期为6-11年。此外，没有可用的治疗方法可以阻止AD的进展。最终，FTD或AD患者将需要全天候医疗护理。颗粒蛋白前体（PGRN）是一种神经营养因子，已被确定为神经退行性疾病的危险因素。PGRN单倍不足是所有FTD病例中10%的原因，而其他等位基因与迟发型AD的发生相关。SORT 1是一种跨膜受体，通过在细胞表面结合PGRN并迅速内化以进行溶酶体降解来控制PGRN的细胞外水平，同时它是PGRN信号转导的受体。我们提出通过开发结合SORT 1、阻断与PGRN的相互作用并因此在体外和体内功能性地升高PGRN水平的抗体来产生可以升高细胞外PGRN水平的治疗剂。有效的先导抗体将针对亲和力和其他特性进行优化，并作为开发候选物进行确证性和临床前试验。在这个项目中产生的数据集和SORT 1抗体将使我们能够获得额外的资金，用于推进候选人进行临床前测试，IND提交和临床。在PGRN突变患者中进行的SORT 1抗体试验将最终确定治疗性PGRN升高是否能如假设的那样在FTD和AD患者中提供有意义的临床获益。

 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.