An Orally Bioavailable Drug Candidate for Spinal Muscular Atrophy

一种治疗脊髓性肌萎缩症的口服生物利用候选药物

• 批准号: 9005317
• 负责人: PETER G SCHULTZ
• 金额: $ 38.19万
• 依托单位: CALIFORNIA INSTITUTE/BIOMEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005317
• 关键词: Adult; Adverse effects; Affinity; Bioavailable; Biological; Brain; Canis familiaris; Cause of Death; Cessation of life; Childhood; Clinical; Clinical Research; Development; Disease; Dose; Drug Kinetics; Exhibits; Frequencies; Gene Expression; Genetic; Goals; Hereditary Disease; In Vitro; Infant; Lead; Length; Life; Modeling; Mus; Muscle Weakness; Muscular Atrophy; Mutation; Neonatal; Neuromuscular Diseases; Neuroprotective Agents; Oral Administration; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Plasma; Positioning Attribute; Proteomics; RNA Splicing; Rattus; Regimen; Role; SMN1 gene; SMN2 gene; Safety; Spinal Muscular Atrophy; Time; Toddler; Toxicology; Transgenic Organisms; Work; analog; brain tissue; cytotoxicity; design; drug candidate; gene product; improved; in vitro activity; motor neuron function; mouse model; pre-clinical; preclinical study; programs; public health relevance

 DESCRIPTION (provided by applicant): Spinal muscular atrophy is a genetic disease resulting from mutations in the SMN1 gene that results in impaired motor neuron function and can lead to death. Currently there are no approved drugs for this debilitating pediatric disease. Our goal is to generate an orally bioavailable drug for the treatment of SMA that upregulates SMN2 gene expression to compensate for the loss of the wild type SMN1 gene. Such drugs can likely be used in combination with the splicing modulators or neuroprotective agents (if approved) that are currently in clinical development to provide increased patient benefit. In preliminary work we have identified a lead compound with excellent in vitro activity and good pharmacokinetics that upregulates SMN levels in the SMN∆7 neonatal mouse model without obvious adverse effects. New analogs will be designed, synthesized and assessed for in vitro activity, cytotoxicity and in vitro ADME and safety profiles. Analogues with improved cellular activity (full-length SMN levels), low cytotoxicity and favorable in vitro safety profiles will be selected for PK studies in adult and neonatal mice. These analogs will also be studied in rat PK models (oral administration, plasma and brain levels at different time points) to assess their pharmacokinetics across different species. Analogs that exhibit favorable brain PK profiles at tolerated doses (without obvious adverse effects in neonatal mice) will be progressed to pharmacodynamic (full-length SMN levels in brain tissue) and efficacy studies in SMNΔ7 neonatal mice. In parallel the biological target of select potent compounds will be identified using affinity probes and the mechanism by which SMN levels are upregulated will be investigated. Finally, once a preclinical candidate is selected (a) the dosing regimen will be optimized including efficacious dose range determination and dosing frequency; (b) a comprehensive set of in vitro physicochemical, ADME and safety profiling studies (detailed in Table 2, vide infra) will be carried out; and (c) th PCC will be assessed in rat and dog pharmacokinetic and toxicology studies. Upon the completion of the proposed studies, we will be positioned to initiate IND-enabling studies for the selected PCC, and move the program forward into clinical studies with an appropriate commercial partner.

 描述（由适用提供）：脊柱肌肉萎缩是由SMN1基因突变引起的遗传疾病，导致运动神经元功能受损并可能导致死亡。目前尚无批准这种使人衰弱的小儿疾病的药物。我们的目标是生成一种口服的可生物利用药物来治疗SMA，该药物上调SMN2基因表达以补偿野生型SMN1基因的损失。此类药物可以与当前正在临床发育中的剪接调节剂或神经保护剂（如果获得批准）结合使用，以提供增加患者的益处。在初步工作中，我们已经确定了具有出色体外活性和良好药代动力学的铅化合物，可在没有明显的不良影响的情况下上调SMNΔ7新生小鼠模型中的SMN水平。将设计，合成和评估新的类似物，以实现体外活性，细胞毒性以及体外ADME和安全概况。将选择改善细胞活性（全长SMN水平），低​​细胞毒性和有利的体外安全剖面的类似物。 成人和新生小鼠。这些类似物还将在大鼠PK模型（在不同时间点口服，血浆和大脑水平）中进行研究，以评估不同物种的药代动力学。在耐受剂量（新生儿小鼠中没有明显的不良反应）下暴露有利的脑PK谱的类似物将发展为药效学（脑组织中的全长SMN水平）和SMNΔ7新生小鼠的有效性研究。可以使用亲和力问题确定所选潜在化合物的生物学靶标，并将研究SMN水平的机制。最后，一旦选择了临床前候选者（a）剂量方案将被优化，包括有效的剂量范围测定和剂量频率； （b）将进行一系列全面的体外物理，ADME和安全分析研究（在表2中详细介绍了Infifra）； （c）将在大鼠和狗药代动力学和毒理学研究中评估PCC。拟议的研究完成后，我们将定位为选定的PCC启动辅助研究，并将该计划与适当的商业伙伴一起前进到临床研究中。