Tetracycline derivatives as SMN2 mRNA splicing modifiers for treatment of SMA.

四环素衍生物作为 SMN2 mRNA 剪接修饰剂，用于治疗 SMA。

• 批准号: 8292087
• 负责人: S.KEN TANAKA
• 金额: --
• 依托单位: PARATEK PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-05 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292087
• 关键词: Acute; Adult; Adverse effects; Animal Model; Anthracyclines; Behavior; Biological Assay; Blood - brain barrier anatomy; Brain; Cardiovascular system; Cells; Characteristics; Chemicals; Chemistry; Chicago; Child; Clinical; Clinical Trials; Deterioration; Development; Disease; Drug Design; Drug Kinetics; Drug usage; Evaluation; Exons; Genes; Goals; Half-Life; Human; In Vitro; Laboratories; Lead; Length; Messenger RNA; Metabolism; Methods; Modeling; Modification; Motor Neurons; Mus; Mutation; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phototoxicity; Plasma; Preparation; Primates; Process; Proteins; Quality of life; RNA Splicing; Renal function; Reporting; Research; Rodent; Rodent Model; Route; SMN2 gene; Safety; Spinal Muscular Atrophy; Structure of purkinje fibers; Structure-Activity Relationship; Testing; Tetracyclines; Therapeutic; Time; Tissues; Toxic effect; Transgenic Mice; Work; analog; brain tissue; chemical stability; cytotoxicity; design; genotoxicity; improved; in vitro Assay; in vitro activity; in vitro testing; in vivo; mRNA Precursor; medical schools; meetings; neonate; novel; pharmacokinetic characteristic; pre-clinical; preclinical safety; preclinical study; preclinical toxicity; prevent; protein expression; research and development; respiratory; scale up

DESCRIPTION (provided by applicant): Project Summary. Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder characterized by progressive deterioration of motor neurons in the CMS. There is no treatment or cure for this disease. SMA is the result of the homozygous mutation or deletion of the SMN1 (survival motor neuron-1) gene which encodes the SMN protein (SMNp) which is necessary for the survival of motor neurons. A nearly identical gene in humans, SMN2, fails to prevent SMA because its pre-mRNA undergoes aberrant splicing resulting in an unstable and non-functional SMNp. Pharmacologic modulation of SMA/2mRNA splicing, resulting in increased expression of full-length SMNp, has been reported for the anthracycline drug class. Paratek Pharmaceuticals proposes to develop a novel tetracycline (TC) compound, which has structural similarity to the anthracycline class, to provide a safe, effective drug for modifying SMN2 splicing and improving motor neuron survival in SMN patients. Previous efforts at Paratek have led to the discovery of a TC having significant splice-modifying activity and which increases the expression of full-length SMN2 mRNA in vitro and in vivo. The goals of the present proposal are to (1) synthesize and characterize new TC derivatives in order to maximize splicemodifying activity, (2) optimize the pharmacokinetic characteristics and in vivo efficacy of these novel TCs, and (3) develop a candidate compound with the ultimate goal of filing an IND for its application as a therapeutic treatment for SMA. Paratek will be collaborating with Adrian Krainer at Cold Spring Harbor Laboratory and Michelle Hastings at Chicago Medical School for this work. The proposed methods will include: (1) testing TC derivatives in a cell-free SMV2mRNA splicing assay; (2) in vitro testing of splice-modifying compounds for increased cellular expression of SMNp; (3) in vivo analysis of PK and brain-penetrating activity of TCs; (4) in vivo testing of selected compounds for increased expression of human S/W/V2mRNA in smn;SMN2 transgenic mice and enhanced survival in smn-/-;SMN2 neonate mice. Compounds having in vivo efficacy will undergo preclinical toxicologic, genotoxic and safety pharmacologic analyses to select a candidate for clinical development. Relevance. The goal is to discover, develop, and bring to clinical trial a tetracycline drug for use in the treatment of spinal muscular atrophy (SMA). The drug is intended to prolong and improve the quality of life for children and adults with SMA, a disease for which there presently is no cure.

描述（申请人提供）：项目摘要。脊柱肌肉萎缩（SMA）是一种常染色体隐性疾病，其特征是CMS中运动神经元的逐渐恶化。这种疾病没有治疗方法。 SMA是SMN1（存活运动神经元）基因的纯合突变或缺失的结果，该基因编码SMN蛋白（SMNP），这对于运动神经元的存活是必需的。人类中几乎相同的基因SMN2无法预防SMA，因为其前MRNA经历了异常的剪接，导致不稳定且非功能性的SMNP。据报道，蒽环类药物类别已经报道了SMA/2MRNA剪接的药理调节，导致全长SMNP的表达增加。 Paratek Pharmaceuticals建议开发一种新型的四环素（TC）化合物，该化合物与Anthracycline类具有结构相似性，以提供一种安全有效的药物，用于修饰SMN2剪接并改善SMN患者的运动神经元生存。 在帕拉特克（Paratek）的先前努力导致发现了具有显着剪接的活性的TC，并在体外和体内增加了全长SMN2 mRNA的表达。本提案的目标是（1）合成和表征新的TC衍生物，以最大程度地提高拼接化的活动，（2）优化这些新型TC的药代动力学特征和体内功效，（3）开发候选化合物，其最终的IND申请以申请其治疗smaa，以实现IND的最终目标。 Paratek将与Cold Spring Harbour Laboratory的Adrian Krainer和芝加哥医学院的Michelle Hastings合作进行这项工作。提出的方法将包括：（1）在无细胞SMV2MRNA剪接测定中测试TC衍生物； （2）剪接修饰化合物的体外测试，以增加SMNP的细胞表达； （3）PK的体内分析和TC的脑穿透活性； （4）在SMN; SMN2转基因小鼠中人类S/W/V2MRNA表达增加的选定化合物的体内测试，并在SMN - / - ; SMN2 Neonate小鼠中增强了生存率。具有体内功效的化合物将经历临床前毒理学，遗传毒性和安全药理学分析，以选择临床发育的候选者。 关联。目的是发现，开发和引入临床试验，用于治疗脊柱肌肉萎缩（SMA）的四环素药物。该药物旨在延长和改善SMA儿童和成人的生活质量，这种疾病目前无法治愈。

项目成果

Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy.

• DOI: 10.1126/scitranslmed.3000208
• 发表时间: 2009-11-04
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Hastings ML;Berniac J;Liu YH;Abato P;Jodelka FM;Barthel L;Kumar S;Dudley C;Nelson M;Larson K;Edmonds J;Bowser T;Draper M;Higgins P;Krainer AR
• 通讯作者: Krainer AR