Treatment of Acid Ceramidase Deficiency

酸性神经酰胺酶缺乏症的治疗

基本信息

批准号：
9354997
负责人：
Sharie Haugabook
金额：
$ 141.71万
依托单位：
NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9354997
关键词：
Animal Model Apoptosis Arthritis Biochemical Biological Assay Bone Marrow Transplantation Cell model Ceramides Cessation of life Clinical Clinical Trials DNA Sequence Alteration Development Dose Employee Strikes Enzymes Equilibrium Farber&apos s lipogranulomatosis Formulation Human Infant Investigational New Drug Application Lead Lipid Bilayers Liver Liver diseases Lung Lung Inflammation Lysosomes Medical Metabolic Metabolic Diseases Musculoskeletal System Natural History Nervous system structure Organ Organelles Patients Pharmaceutical Preparations Procedures Process Progressive Myoclonic Epilepsies Proteins Recombinants Research Personnel Risk Safety Scientist Spinal Muscular Atrophy Spleen Technology Therapeutic Therapeutics for Rare and Neglected Diseases Tissues Toxicology United States Food and Drug Administration body system cell injury effective therapy enzyme activity enzyme replacement therapy galactosylgalactosylglucosylceramidase in vivo macrophage pre-clinical preclinical study premature

项目摘要

Ceramides are present at high concentrations in the cellular lipid bilayer across a range of tissues and organs, including the liver, spleen, musculoskeletal system, and lungs. Loss of acid ceramidase (AC) enzyme activity leads to toxic accumulation of ceramide in lysosomes and other organelles. Although macrophages can take up cells damaged by ceramide accumulation, they are unable to process the toxic ceramide itself. This inability results in a cascade of cell damage and apoptosis across these multiple tissues and organ systems. Enzyme replacement therapy is a well-established approach to treating metabolic disorders. The investigators at Plexcera have shown in patient-derived cellular models and animal models of Farbers disease that a recombinant human acid ceramidase (rhAC) is able to break down the accumulated ceramide to normal levels in some tissues. This rhAC therapeutic approach represents a platform technology with the potential to treat not only Farbers disease but also other rare conditions driven by lack of AC activity for which there are no effective therapies, such as spinal muscular atrophy with progressive myoclonic epilepsy. The TRND project team have developed a project plan encompassing the pre-clinical studies necessary to enable submission of an Investigational New Drug application with the Food and Drug Administration. The plan includes developing a suitable formulation of rhAC to facilitate clinical dosing, conducting toxicology studies to demonstrate drug safety, developing and validating the biochemical assays necessary to evaluate the drug product and its in vivo activity, and conducting patient-finding activities to facilitate a natural history study and eventual clinical trials.

神经酰胺以高浓度存在于细胞脂质双层，包括肝脏，脾脏，肌肉骨骼系统和肺部。酸性神经酶（AC）酶活性的丧失导致神经酰胺在溶酶体和其他细胞器中的有毒积累。尽管巨噬细胞可以吸收神经酰胺积累破坏的细胞，但它们无法处理有毒的神经酰胺本身。这种无法在这些多个组织和器官系统中导致一系列细胞损伤和凋亡。酶替代疗法是治疗代谢疾病的良好方法。 Plexcera的研究人员已经在患者来源的细胞模型和远见疾病的动物模型中表明，重组人酸神经酰胺酶（RHAC）能够将累积的神经酰胺分解为某些组织中的正常水平。这种RHAC治疗方法代表了一种平台技术，它不仅可以治疗疾病，而且还可以通过缺乏有效疗法的AC活性驱动的其他罕见疾病，例如脊髓肌萎缩症和进行性肌阵挛性癫痫。 TRND项目团队制定了一项项目计划，其中涵盖了临床前研究，以便向食品药品监督管理局提交研究性新药应用。该计划包括开发合适的RHAC制定，以促进临床给药，进行毒理学研究，以证明药物安全，开发和验证评估药物及其体内活性所需的生化测定，并进行患者发现活动以促进自然历史研究和最终临床试验。