MTR1: A Dinucleotide Substrate Enhancement and Molecular ByPass Therapy for Thymidine Kinase 2 Deficiency

MTR1：针对胸苷激酶 2 缺乏症的二核苷酸底物增强和分子旁路疗法

基本信息

批准号：
10705703
负责人：
Ward Peterson
金额：
$ 89.77万
依托单位：
MITORAINBOW THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-17 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705703
关键词：
2&apos -Deoxythymidine Acute Adult Adverse effects Biological Assay Biological Availability Breathing Bypass Child Childhood Clinical Clinical Trials DNA DNA biosynthesis Data Deglutition Deglutition Disorders Deoxycytidine Diagnosis Diarrhea Dinucleoside Phosphates Disease Disease Progression Dose Drug Combinations Drug Kinetics Eating Effectiveness Enteral Feeding Enzymes Equilibrium Event Family suidae Formulation Genetic Goals Hereditary Disease Impairment Individual Infant Ingestion Miniature Swine Mitochondria Mitochondrial DNA Molecular Movement Muscle Cells Muscle function Myopathy Nausea No-Observed-Adverse-Effect Level Nucleosides Nucleotides Oral Oral Administration Pathogenesis Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Study Phase Phosphorylation Plasma Prodrugs Production Pyrimidine Pyrimidine Nucleosides Pyrimidine Nucleotides Qualifying Rattus Respiratory Diaphragm Respiratory Insufficiency Route Safety Seizures Skeletal Muscle Small Business Innovation Research Grant Solubility Subcutaneous Injections TRPM5 gene Therapeutic Thymidine Kinase Titrations Toddler Toxic effect Toxicology Translations Vomiting clinical development clinical investigation effective therapy first-in-human frailty functional loss gastrointestinal system genotoxicity improved in vivo infancy manufacture monomer nervous system disorder parenteral administration patient subsets pre-clinical preclinical development programs prototype respiratory safety study small molecule subcutaneous tripolyphosphate

项目摘要

SUMMARY Thymidine Kinase 2 (TK2) is a mitochondrial enzyme that performs the first of the sequential phosphorylation steps that produce deoxythymidine triphosphates and deoxycytidine triphosphates, which are required for mitochondrial DNA synthesis. Genetic deficiency of TK2 results in depletion of mitochondrial DNA and loss of functional mitochondria. These events result in TK2 deficiency, a disease that manifests as progressive myopathy, primarily of skeletal muscle and the diaphragm, and occasional neurological disorders such as seizures. The most aggressive form of the disease has its onset in infancy, and most of these toddlers die within a year of diagnosis. Elucidation of the pathogenesis of TK2 deficiency has led to two potential treatment options that were evaluated under a compassionate use program: (1) substrate enhancement therapy and (2) molecular bypass therapy. Substrate enhancement therapy consists of administering combinations of deoxycytidine and deoxythymidine (dC+dT) and molecular bypass therapy consists of administering combinations of dC monophosphate and dT monophosphate (dCMP+dTMP). Either combination pair was shown to reverse disease progression and lengthen the lives of patients with TK2 deficiency. The combination of dC+dT is currently in clinical development and is administered at very high doses (ranging from approximately 8 to >50 grams daily) in patients who have difficulty swallowing, a subset of whom require feeding tubes to eat. Furthermore, dC+dT offers the benefit of substrate enhancement therapy, but not molecular bypass therapy. MitoRainbow is pursuing preclinical development of a MTR1, a single-agent dinucleotide that is metabolized to all four therapeutic compounds (dC, dT, dCMP and dTMP) in vivo, thus providing both substrate enhancement and molecular bypass therapies. MTR1 is administered by parenteral administration at <1% the dose of oral dT+dC. This approach is anticipated to provide superior bioavailability and ease of use to reach the threshold of effectiveness to treat TK2 deficiency. In this Direct-to-Phase II SBIR we will (1) manufacture MTR1 drug substance (Aim 1), (2) perform a preclinical, non-GLP PK, and acute tolerability study in minipigs (Aim 2), and (3) conduct IND-enabling bioanalytical, PK, and safety studies (Aim 3). Completion of these Aims will provide sufficient data for MitoRainbow to file an IND with the FDA, and to initiate clinical investigations of MTR1 drug product in patients with TK2 deficiency.

概括胸苷激酶 2 (TK2) 是一种线粒体酶，执行第一个顺序磷酸化产生脱氧胸苷三磷酸和脱氧胞苷三磷酸的步骤，这是线粒体DNA合成。 TK2 遗传缺陷导致线粒体 DNA 耗尽和线粒体 DNA 丧失功能性线粒体。这些事件导致 TK2 缺乏，这种疾病表现为进行性肌病，主要是骨骼肌和膈肌，以及偶尔的神经系统疾病，例如癫痫发作。这种疾病最具侵袭性的形式在婴儿期发病，大多数幼儿在婴儿期就死亡。诊断一年。 TK2 缺陷发病机制的阐明导致了两种潜在的治疗方案的评估根据同情使用计划：(1) 基质增强疗法和 (2) 分子旁路疗法。底物增强疗法包括给予脱氧胞苷和脱氧胸苷的组合 (dC+dT) 和分子旁路疗法包括给予 dC 单磷酸盐和 dT 的组合单磷酸盐（dCMP+dTMP）。任一组合均被证明可以逆转疾病进展，并且延长 TK2 缺乏症患者的生命。 dC+dT组合目前正处于临床开发阶段并以非常高的剂量（每天约 8 至 >50 克）给予患有以下疾病的患者：吞咽困难，其中一部分人需要饲管才能进食。此外，dC+dT 的优点是底物增强疗法，但不是分子旁路疗法。 MitoRainbow 正在致力于 MTR1 的临床前开发，MTR1 是一种单药二核苷酸，可代谢为所有四种治疗化合物（dC、dT、dCMP 和 dTMP）在体内，从而提供底物增强和分子旁路疗法。 MTR1 通过胃肠外给药，剂量<口服剂量的 1% dT+dC。这种方法预计将提供卓越的生物利用度和易用性以达到阈值治疗 TK2 缺乏症的有效性。在此直接进入 II 期 SBIR 中，我们将 (1) 制造 MTR1 原料药（目标 1），(2) 进行临床前、在小型猪中进行非 GLP PK 和急性耐受性研究（目标 2），以及 (3) 进行支持 IND 的生物分析、PK、和安全研究（目标 3）。完成这些目标将为 MitoRainbow 提交 IND 提供足够的数据与 FDA 合作，并启动 MTR1 药品在 TK2 缺陷患者中的临床研究。