A Small Molecule Enzyme Replacement for the Treatment of CLN1

用于治疗 CLN1 的小分子酶替代品

• 批准号: 10325648
• 负责人: Neal Krishna Devaraj
• 金额: $ 46.71万
• 依托单位: PALM THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325648
• 关键词: Address; Affect; Apoptosis; Binding; Biological; Biological Assay; Biology; Birth; Blindness; Blood - brain barrier anatomy; CLN1 gene; Cell Line; Cell Survival; Cell model; Cells; Characteristics; Chemicals; Chemistry; Child; Childhood; Cleaved cell; Collection; Coupling; Data; Development; Disease; Disease model; Dose; Engineering; Enzymes; Fibroblasts; Foundations; Genes; Goals; Heart; Hepatocyte; Hereditary Disease; In Vitro; Joints; Lead; Life Expectancy; Lipids; Lysosomes; Membrane; Methods; Microscopy; Mission; Modeling; Monitor; Morphology; Mus; Neuraxis; Neurodegenerative Disorders; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plant Resins; Positioning Attribute; Preclinical Testing; Proteins; Recovery; Replacement Therapy; Research Personnel; Seizures; Serum; Skeletal system; Small Business Innovation Research Grant; Solubility; Stains; Symptoms; Systemic Therapy; Tail; Technology; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Western Blotting; Work; base; blood-brain barrier permeabilization; cerebral atrophy; commercialization; disease phenotype; drug development; efficacy evaluation; efficacy study; experience; improved; in vivo; in vivo evaluation; innovation; lipophilicity; loss of function mutation; lysosomal proteins; mouse model; neuromuscular; neuron loss; neurotoxicity; novel; palmitoylation; preclinical evaluation; preclinical study; response; scaffold; screening; small molecule; thioester; thioesterase PPT1 gene product; Address; Affect; Apoptosis; Binding; Biological; Biological Assay; Biology; Birth; Blindness; Blood - brain barrier anatomy; CLN1 gene; Cell Line; Cell Survival; Cell model; Cells; Characteristics; Chemicals; Chemistry; Child; Childhood; Cleaved cell; Collection; Coupling; Data; Development; Disease; Disease model; Dose; Engineering; Enzymes; Fibroblasts; Foundations; Genes; Goals; Heart; Hepatocyte; Hereditary Disease; In Vitro; Joints; Lead; Life Expectancy; Lipids; Lysosomes; Membrane; Methods; Microscopy; Mission; Modeling; Monitor; Morphology; Mus; Neuraxis; Neurodegenerative Disorders; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plant Resins; Positioning Attribute; Preclinical Testing; Proteins; Recovery; Replacement Therapy; Research Personnel; Seizures; Serum; Skeletal system; Small Business Innovation Research Grant; Solubility; Stains; Symptoms; Systemic Therapy; Tail; Technology; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Western Blotting; Work; base; blood-brain barrier permeabilization; cerebral atrophy; commercialization; disease phenotype; drug development; efficacy evaluation; efficacy study; experience; improved; in vivo; in vivo evaluation; innovation; lipophilicity; loss of function mutation; lysosomal proteins; mouse model; neuromuscular; neuron loss; neurotoxicity; novel; palmitoylation; preclinical evaluation; preclinical study; response; scaffold; screening; small molecule; thioester; thioesterase PPT1 gene product

PROJECT SUMMARY Significance: CLN1 is a devastating neurodegenerative disorder affecting 1 in 100,000 children born worldwide. This untreatable disease is characterized by dramatic developmental decline, neuromuscular symptoms, vision loss, and neuronal death. Unfortunately, patients with this disease rarely survive past childhood. CLN1 is the result of a loss-of-function mutation in the gene PPT1 that encodes for the enzyme palmitoyl-protein thioesterase 1 (PPT1). PPT1 is a lysosomal enzyme responsible for removing S-palmitoyl groups from proteins. When it is dysfunctional, as is the case with CLN1, lipids and proteins accumulate in cells and have toxic effects in the central nervous system, heart, and skeletal system. There are currently no approved therapies for CLN1, and children with this disease experience an average life expectancy of 8-12 years. Objective: To address the critical unmet need for CLN1 therapeutics, we are developing the first small molecule PPT1 replacement therapy for systemic treatment of this disease. We have recently engineered a novel class of depalmitoylating molecules (DPALMs), which chemoselectively cleave S-palmitoyl groups from proteins in live cells. Using this technology, we aim to develop compounds that can restore PPT1-like thioesterase activity to CLN1 cells. Preliminary Data: We have identified a set of DPALM lead compounds that effectively depalmitoylate PPT1 substrates and reverse abnormal protein accumulation in CLN1 patient-derived cells. Furthermore, we found that DPALMs are effective at non-toxic doses and are well tolerated in vivo. Specific Aims: We will optimize the potency and drug-like characteristics of our lead compounds to generate a DPALM suitable for preclinical testing and IND enabling studies. In SPECIFIC AIM 1, we will generate a set of optimized DPALMs using joint synthesis and screening efforts. A modular and robust synthetic strategy will be used to generate new compounds, which will then be screened for depalmitoylation activity toward PPT1 substrates. In SPECIFIC AIM 2, we will evaluate the efficacy of optimized DPALMs in CLN1 model cell lines. Compounds will be tested for their ability to reduce the level of accumulated proteins, reverse abnormal lysosome morphology, and inhibit apoptosis in in vitro disease models. The proposed studies will enable the development of a highly active DPALM and accelerate the commercialization of this therapy for the treatment of CLN1.

项目摘要 意义：CLN1是一种毁灭性的神经退行性疾病，影响了全世界出生的100,000名儿童中有1个。 这种不可治疗的疾病的特征是发育的急剧下降，神经肌肉症状，视力 损失和神经元死亡。不幸的是，这种疾病的患者过去很少能在童年时期生存。 Cln1是 编码酶棕榈酰蛋白硫酯酶的基因PPT1的功能丧失突变的结果 1（ppt1）。 PPT1是一种溶酶体酶，负责从蛋白质中去除s-甲米酰基。何时 功能失调，与CLN1一样，脂质和蛋白质在细胞中积累，并在该细胞中具有毒性作用 中枢神经系统，心脏和骨骼系统。目前尚无针对CLN1的批准疗法， 患有这种疾病的儿童的平均预期寿命为8-12岁。目的：解决 对CLN1治疗剂的关键需求未满足，我们正在开发第一个小分子PPT1替代疗法 用于全身治疗该疾病。我们最近设计了一类新型的脱木米粉分子 （DPALMS），从活细胞中的蛋白质裂解S-膜酰基基团的化学选择性。使用此技术， 我们旨在开发可以将PPT1样硫酯酶活性恢复到CLN1细胞的化合物。初步数据： 我们已经确定了一组DPALM铅化合物，这些化合物有效地depalmitoylate PPT1底物和反向 CLN1患者衍生细胞中蛋白质异常的积累。此外，我们发现DPALM是有效的 以无毒剂量，体内耐受性良好。具体目的：我们将优化效力和毒品样 我们的铅化合物的特征以生成适合临床前测试和IND启用的DPALM 研究。在特定目标1中，我们将使用关节合成和筛选生成一组优化的DPALM 努力。将使用模块化且坚固的合成策略来生成新化合物，然后将是 筛选对ppt1底物的去氨酰二酰化活性。在特定目标2中，我们将评估功效 CLN1模型细胞系中优化的DPALM。化合物将通过降低水平的能力进行测试 积累的蛋白质，反向异常溶酶体形态和抑制体外疾病模型中的凋亡。 拟议的研究将使高度活跃的DPAL的发展并加速 该疗法用于治疗CLN1的商业化。