Blain Jean-François, Bursavich Matthew G, Freeman Emily A, Hrdlicka Lori A, Hodgdon Hilliary E, Chen Ting, Costa Don E, Harrison Bryce A, Kapadnis Sudarshan, Murphy Deirdre A, Nolan Scott, Tu Zhiming, Tang Cuyue, Burnett Duane A, Patzke Holger, Koenig Gerhard
FORUM Pharmaceuticals Inc, 225 2nd Avenue, Waltham, MA, 02451, USA.
Alzheimers Res Ther. 2016 Aug 30;8(1):34. doi: 10.1186/s13195-016-0199-5.
Familial Alzheimer's disease (FAD) is caused by mutations in the amyloid precursor protein (APP) or presenilin (PS). Most PS mutations, which account for the majority of FAD cases, lead to an increased ratio of longer to shorter forms of the amyloid beta (Aβ) peptide. The therapeutic rationale of γ-secretase modulators (GSMs) for Alzheimer's disease is based on this genetic evidence as well as on enzyme kinetics measurements showing changes in the processivity of the γ-secretase complex. This analysis suggests that GSMs could potentially offset some of the effects of PS mutations on APP processing, thereby addressing the root cause of early onset FAD. Unfortunately, the field has generated few, if any, molecules with good central nervous system (CNS) drug-like properties to enable proof-of-mechanism studies.
We characterized the novel GSM FRM-36143 using multiple cellular assays to determine its in vitro potency and off-target activity as well as its potential to reverse the effect of PS mutations. We also tested its efficacy in vivo in wild-type mice and rats.
FRM-36143 has much improved CNS drug-like properties compared to published GSMs. It has an in vitro EC50 for Aβ42 of 35 nM in H4 cells, can reduce Aβ42 to 58 % of the baseline in rat cerebrospinal fluid, and also increases the non-amyloidogenic peptides Aβ37 and Aβ38. It does not inhibit Notch processing, nor does it inhibit 24-dehydrocholesterol reductase (DHCR24) activity. Most interestingly, it can reverse the effects of presenilin mutations on APP processing in vitro.
FRM-36143 possesses all the characteristics of a GSM in terms of Aβ modulation Because FRM-36143 was able to reverse the effect of PS mutations, we suggest that targeting patients with this genetic defect would be the best approach at testing the efficacy of a GSM in the clinic. While the amyloid hypothesis is still being tested with β-site APP-cleaving enzyme inhibitors and monoclonal antibodies in sporadic AD, we believe it is not a hypothesis for FAD. Since GSMs can correct the molecular defect caused by PS mutations, they have the promise to provide benefits to the patients when treated early enough in the course of the disease.
家族性阿尔茨海默病（FAD）由淀粉样前体蛋白（APP）或早老素（PS）的突变引起。大多数导致FAD病例的PS突变会使淀粉样β（Aβ）肽的长形式与短形式的比例增加。γ-分泌酶调节剂（GSMs）治疗阿尔茨海默病的理论依据基于这一遗传学证据以及酶动力学测量结果，这些结果显示γ-分泌酶复合物的持续加工能力发生了变化。该分析表明，GSMs可能会抵消PS突变对APP加工的一些影响，从而解决早发性FAD的根本原因。不幸的是，该领域几乎没有产生具有良好中枢神经系统（CNS）类药物特性的分子来进行机制验证研究。
我们使用多种细胞分析方法对新型GSM FRM-36143进行了表征，以确定其体外效力、脱靶活性以及逆转PS突变影响的潜力。我们还在野生型小鼠和大鼠体内测试了其疗效。
与已发表的GSMs相比，FRM-36143具有显著改善的CNS类药物特性。它在H4细胞中对Aβ42的体外半数有效浓度（EC50）为35 nM，可将大鼠脑脊液中的Aβ42降低至基线的58%，还能增加非淀粉样生成肽Aβ37和Aβ38。它不抑制Notch加工，也不抑制24-脱氢胆固醇还原酶（DHCR24）的活性。最有趣的是，它可以在体外逆转早老素突变对APP加工的影响。
就Aβ调节而言，FRM-36143具有GSM的所有特征。由于FRM-36143能够逆转PS突变的影响，我们认为针对具有这种遗传缺陷的患者进行治疗将是在临床上测试GSM疗效的最佳方法。虽然淀粉样蛋白假说仍在散发性AD中通过β-位点APP裂解酶抑制剂和单克隆抗体进行验证，但我们认为它不适用于FAD。由于GSMs可以纠正由PS突变引起的分子缺陷，它们有望在疾病过程中尽早治疗时为患者带来益处。
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