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Postnatal and Prenatal Therapeutic Base Editing for Metabolic Diseases

代谢性疾病的产后和产前治疗碱基编辑

基本信息

批准号：
10668614
负责人：
Kiran Musunuru
金额：
$ 641.57万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668614
关键词：
ANGPTL3 gene Address Adenine Anaphylaxis Animal Model Animals Antibodies Area Bacteria Biodistribution Birth CRISPR/Cas technology Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats DNA Dependovirus Development Disease Dose Drug Kinetics Enzymes Funding Gene Mutation Genes Genetic Diseases Goals Guide RNA Health Heart Hematopoietic Stem Cell Transplantation Hemoglobinopathies Hepatocyte Hereditary Disease Human Injectable Intravenous Joints Lead Life Liver Lung Medical Metabolic Metabolic Diseases Modality Modeling Morbidity - disease rate Mucopolysaccharidoses Mus Mutation Neurologic Nucleotides Organ Outcome Pathogenicity Patients Pharmaceutical Preparations Pharmacology and Toxicology Phase I/II Clinical Trial Phenotype Phenylketonurias Primates Process Publishing Research Activity Research Project Grants Resources Sheep Technology Therapeutic Time Tissue Sample Treatment Efficacy Tyrosinemias Variant Writing adeno-associated viral vector animal resource base editing base editor cancer immunotherapy chimeric antigen receptor T cells efficacy testing enzyme replacement therapy fetal gene correction genome editing human model humanized mouse improved in utero in vivo lead optimization lipid nanoparticle meetings mortality mortality risk non-compliance nonhuman primate novel novel therapeutics nuclease pharmacologic postnatal pre-Investigational New Drug meeting preclinical study prenatal prime editing programs response somatic cell gene editing success targeted treatment therapeutic genome editing timeline tool treatment strategy

项目摘要

PROJECT SUMMARY The potential for the development of novel therapeutic modalities has energized the genome editing field since it first emerged in the 1990s and especially since the demonstration of programmable genome editing with CRISPR-Cas9 by multiple groups in 2012. There has been substantial progress with ex vivo therapeutic applications of genome editing in patients in the past few years, most notably with CAR-T immunotherapies for cancer and with durable treatment of hemoglobinopathies. Progress with in vivo therapeutic applications, i.e., somatic cell genome editing, has been slower due to the technical challenges inherent in the delivery of genome- editing tools into the body. As of the time of this writing, there are few published examples of successful genome editing performed in vivo in primates (including humans), with almost all examples involving somatic genome editing in the liver: TTR with Cas9 nuclease delivered by lipid nanoparticles (LNPs), PCSK9 and ANGPTL3 with adenine base editors delivered by LNPs, and PCSK9 with meganucleases delivered by adeno-associated virus (AAV) vectors. The prospects for genome-editing therapies extend to before birth, with in utero genome editing having the potential to treat genetic diseases that result in significant morbidity and mortality before or shortly after birth. Although restricted to small animal models so far, in utero genome editing has proven effective in the liver, lungs, heart, and other organs. Our Overall Program seeks to build on these early successes, pursuing goals that that would be of major impact in advancing the field of therapeutic genome editing. Our three Research Projects seek to develop base-editing therapies targeting the liver in order to treat three rare metabolic genetic diseases: phenylketonuria (PKU), hereditary tyrosinemia type 1 (HT1), and mucopolysaccharidosis type 1 (MPSI). Lead Project 1 will focus on LNP-based postnatal treatment of PKU, with the aim to file an IND application by the end of the five-year funding period and begin a phase 1/2 clinical trial soon afterwards. Project 2 will focus on LNP-based postnatal treatment of HT1, with the aim to file an IND application and begin a clinical trial, and prenatal treatment of HT1, with the aim of performing preclinical studies during the five-year funding period to enable an eventual IND application if the postnatal clinical trial proves successful. Project 3 will focus on AAV-based postnatal and prenatal treatment of MPSI, with similar aims as Project 2. Unique, specialized Resource Cores focused on off-target editing and in utero treatment of small and large animals will be indispensable in achieving these aims.

项目总结