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

• 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
• 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' -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

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，执行顺序磷酸化的第一个酶 产生三磷酸脱氧胸苷和三磷酸脱氧胸苷的步骤，这是必需的 线粒体DNA合成。 TK2的遗传缺乏会导致线粒体DNA的耗竭和丧失 功能性线粒体。这些事件导致TK2缺乏症，这种疾病表现为进行性 肌病，主要是骨骼肌和隔膜，以及偶尔的神经系统疾病，例如 癫痫发作。该疾病最具侵略性的形式在婴儿期开始，大多数这些幼儿死亡 一年的诊断。 TK2缺乏症的发病机理的阐明导致了两种潜在的治疗选择 在同情的使用计划下：（1）底物增强疗法和（2）分子旁路治疗。 底物增强疗法包括施用脱氧胞苷和脱氧胸苷的组合 （DC+DT）和分子旁路治疗包括施用DC单磷酸和DT的组合 单磷酸（DCMP+DTMP）。证明两组的组合对逆转疾病的进展和 延长TK2缺乏症患者的寿命。 DC+DT的组合目前正在临床开发中 并以非常高的剂量给药（每天约8至50克） 吞咽困难，其中一部分需要进食管。此外，DC+DT提供了好处 底物增强疗法，但不是分子旁路治疗。 Moritorainbow正在追求MTR1的临床前开发，这是一种被代谢为单一的二核苷酸 体内所有四种治疗化合物（DC，DT，DCMP和DTMP），从而提供两种底物增强 和分子旁路疗法。 MTR1由肠胃外给药以<1％的口服剂量施用 DT+DC。预计这种方法将提供出色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。 在这个直接到相的II SBIR中，我们将（1）生产MTR1药物（AIM 1），（2）进行临床前， 非GLP PK和Minipigs中的急性耐受性研究（AIM 2），（3）进行辅助生物分析，PK， 和安全研究（目标3）。这些目标的完成将为moritorainbow提供足够的数据以提交IND 使用FDA，并在TK2缺乏症患者中启动MTR1药物产品的临床研究。