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Antisense oligonucleotide treatment for Pompe disease

庞贝病的反义寡核苷酸治疗

基本信息

批准号：
10652582
负责人：
VIRGINIA Eunice KIMONIS
金额：
$ 17.27万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2022-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652582
关键词：
Address Age Age Months Antisense Oligonucleotides Applications Grants Autophagocytosis Base Pairing Binding Cardiomyopathies Clinical Trials Combined Modality Therapy Control Groups Cytoplasm DNA Sequence Data Dose Drug Delivery Systems Early treatment Enzymes Evaluation Fabry Disease Fibrosis Future Gaucher Disease Genes Genetic Diseases Glucan 1,4-alpha-Glucosidase Glycogen Glycogen (Starch) Synthase Glycogen Storage Disease Glycogen storage disease type II Goals Government Heart Histologic Histology Human Impairment In Vitro Knock-out Lead Lysosomal Storage Diseases Lysosomes Measurement Measures Mediating Messenger RNA Mus Muscle Muscle Weakness Muscle function Myocardium Myopathy Outcome Pathologic Patients Persons Pharmacologic Substance Production RNA Recombinants Residual state Respiratory Diaphragm Single-Stranded DNA Skeletal Muscle Spinal Muscular Atrophy Technology Testing Therapeutic Tissue Stains Tissues Treatment Efficacy Wild Type Mouse Work clinical application design drug efficacy effective therapy efficacy evaluation efficacy study enzyme activity enzyme replacement therapy gene replacement improved innovation knock-down mouse model muscle degeneration muscle strength novel preclinical study prevent response small molecule standard of care success translational study treatment group treatment strategy

项目摘要

Project Abstract: Pompe disease is a devastating myopathy resulting from the deficiency of the lysosomal enzyme acid alpha- glucosidase (GAA),resulting in accumulation of glycogen in lysosomes and cytoplasm. The standard of care is enzyme replacement therapy (ERT) with recombinant human (rh) GAA. Patients with Pompe disease often have poor outcomes due to limited efficacy of the drug in clearing muscle glycogen stores. Substrate Reduction Therapy (SRT) is effective in other lysosomal storage diseases such as Gaucher and Fabry disease. We propose that by knocking down glycogen synthase (GSY1), we will reduce glycogen synthesis in muscle, thus reducing the amount of substrate requiring to be cleared by enzyme. Our long-term goal is to develop a potent therapy to stop/reduce the progression of the muscle disease in Pompe disease. Major gaps: Despite ERT, patients continue to accumulate glycogen in lysosomes leading to muscle fibrosis and fatty replacement. Effective therapy for the progressive muscle weakness of Pompe disease is thus a huge unmet need. Preliminary results: Antisense Oligonucleotides (ASO) technology has emerged as a powerful direct therapeutic alternative to conventional small molecule approaches or gene replacement strategies for the treatment of genetic disorders such as spinal muscular atrophy. ASOs are short, synthetic single-stranded DNA sequences designed to target RNA by well-characterized Watson-Crick base pairing, and once bound to the target RNA, can modulate RNA function through a degradative mechanism using RnaseH1. Ionis Pharmaceuticals designed and screened ASOs targeting mouse GYS1 in vitro to identify the most efficacious ASO. The lead ASOs from the screen were validated in a dose response study and the top 10 ASOs were screened for testing in wild type mice. Three GYS1 ASOs showed the best tolerability and efficacy profile leading to knock down of GYS1 mRNA by approximately 50% of control. Preclinical studies of the effects of the GYS1 ASOs 25 mg/kg/weekly on muscle glycogen, histology, and muscle function in 1 month and 3-month-old Pompe mice indicated that GYS1 ASOs were effective in knocking down GYS1 by approximately 85%, with approximately 50% improvement in clearing muscle glycogen levels. We therefore believe that early reduction of glycogen substrate or a combination therapy with ERT may be the key to successful treatment in Pompe disease. Hypothesis: We propose that GYS1 ASOs in Pompe mice will reduce glycogen production and prevent muscle weakness, either as monotherapy if started early, or in combination with ERT, to obtain maximum therapeutic benefit. Specific Aims: Aim 1: Identification of the most effective ASO-mediated glycogen synthase (GYS1) knock down to prevent glycogen accumulation in a mouse model of Pompe disease. Aim 2: Correction of muscle glycogen and weakness using GYS1 antisense oligonucleotides in combination with Enzyme Replacement Therapy (ERT) in Pompe mice. Success with this translational study will pave the way for novel effective treatments for Pompe disease.

项目简介: