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

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 CLN 1是一种毁灭性的神经退行性疾病，影响全世界每10万名出生的儿童中就有1名。 这种无法治愈的疾病的特点是戏剧性的发展下降，神经肌肉症状，视力 损失和神经元死亡。不幸的是，患有这种疾病的患者很少能活过童年。CLN 1是 这是由于编码棕榈酰蛋白硫酯酶的基因PPT 1发生功能缺失突变所致 1（PPT1）。PPT 1是一种溶酶体酶，负责从蛋白质中去除S-棕榈酰基。时 如CLN 1的情况，脂质和蛋白质在细胞中积累，并在细胞中具有毒性作用。 中枢神经系统心脏和骨骼系统目前还没有针对CLN 1的获批疗法， 患有这种疾病的儿童平均预期寿命为8-12年。目标：解决 CLN 1治疗的关键未满足的需求，我们正在开发第一个小分子PPT 1替代疗法 用于这种疾病的系统治疗。我们最近设计了一类新型的脱棕榈酰化分子 （DPALMs），其化学选择性地从活细胞中的蛋白质裂解S-棕榈酰基。利用这项技术， 我们的目标是开发能够恢复CLN 1细胞的PPT 1样硫酯酶活性的化合物。初步数据： 我们已经鉴定了一组DPALM先导化合物，其有效地使PPT 1底物脱棕榈酰化并逆转PPT 1的活性。 CLN 1患者来源的细胞中的异常蛋白质积累。此外，我们发现DPALMs是有效的 在无毒剂量下，并且在体内耐受良好。具体目标：我们将优化效价和药物样 我们的先导化合物的特性，以产生适合临床前测试和IND使能的DPALM 问题研究在SPECIFIC AIM 1中，我们将使用联合合成和筛选来生成一组优化的DPALM 努力一个模块化和强大的合成策略将用于产生新的化合物，然后将 筛选对PPT 1底物的脱棕榈酰化活性。在具体目标2中，我们将评估 优化的DPALMs在CLN 1模型细胞系中的作用。将测试化合物降低体内代谢水平的能力。 在体外疾病模型中，本发明的化合物可用于抑制蛋白质积累、逆转异常溶酶体形态并抑制细胞凋亡。 拟议的研究将能够开发一种高活性的DPALM，并加速 用于治疗CLN 1的这种疗法的商业化。