Models and Gene Therapies for AAT Deficiency

AAT 缺乏症的模型和基因疗法

• 批准号: 10463802
• 负责人: Terence R. Flotte
• 金额: $ 267.67万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-09 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463802
• 关键词: Address; Adenine; Affinity; Alleles; Animal Model; Antibody Response; Antigen Receptors; Biodiversity; Biological Assay; Biological Markers; CRISPR/Cas technology; Capsid; China; Chronic Obstructive Pulmonary Disease; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Cryoelectron Microscopy; Deaminase; Densitometry; Disease; Disease model; Doctor of Philosophy; Elastin; Environment; Enzymes; European; Exhibits; Faculty; Ferrets; Future; Gene Silencing; Gene Transduction Agent; Genes; Genetic; Genetic Diseases; Homozygote; Human; Human Genetics; Hybrids; Immune Evasion; Immune response; Immunology; Impairment; Interferon Type II; Laboratories; Lead; Libraries; Life; Liver; Lung; Lung CAT Scan; Lung diseases; Measurement; Measures; Mechanics; Mediating; Modeling; Molecular; Mus; Muscle; Mutation; Other Genetics; Outcome; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Population; Property; Proteins; Pulmonary Emphysema; Pulmonary Inflammation; RNA-Directed DNA Polymerase; Recombinant adeno-associated virus (rAAV); Regulatory T-Lymphocyte; Research Personnel; Role; Safety; Serotyping; Serum; Site; Structure-Activity Relationship; System; Technology; Testing; Time; Transducers; Transgenes; Transgenic Animals; Transgenic Organisms; Variant; Veterinary Medicine; Veterinary Schools; Wild Type Mouse; adeno-associated viral vector; airway obstruction; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; base; base editing; base editor; cell mediated immune response; clinically relevant; collaborative environment; comparative efficacy; delivery vehicle; design; enzyme activity; enzyme linked immunospot assay; gene delivery system; gene replacement; gene therapy; immunogenic; immunoregulation; improved; innovation; mouse model; mutant; neutralizing antibody; neutralizing monoclonal antibodies; new technology; next generation; nonhuman primate; novel; prime editing; prime editor; programs; reconstitution; response; screening; success; tool; treatment response; vector

Project Summary (OVERALL) Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene. The E342K (PI*Z) mutant allele is very common among those of European ancestry, and E342K homozygotes encode a protein with impaired secretion, resulting in deficient AAT serum levels. Since AAT normally protects elastin in the lung from degradation, loss of effective AAT triggers lung inflammation, airways obstruction and emphysema, which is the primary life-limiting manifestation of AATD. The projects within this proposal seek to pursue numerous parallel strategies to develop a gene therapy for AATD. Most of these strategies revolve around the use of recombinant adeno-associated virus (rAAV)-based vectors, a platform technology that has been very successful for other genetic diseases. In Project 1, optimized rAAV vectors will be studied in genetically defined animal models (including mice and ferrets) in comparison with transgenic reconstitution studies using a regulated conditional transgenic system to compare two relevant potential target replacement levels (11µM and 25µM) and clinically relevant endpoints will be studied. In Project 2, novel CRISPR variants will be used for gene editing, base editing and prime editing strategies to treat AATD. In Project 3, we will screen naturally occurring AAV capsid libraries obtained from remote populations in Western China to identify capsids with enhanced efficacy and safety for AATD gene therapy. Finally, in project 4, we will use novel Treg and CAR-Treg strategies to selectively modulate anti-vector immune responses. There will also be two cores. Core A will provide each project with important Vector Immunology assays, which can identify limitations due to host immune responses to AAV capsids, the AAT transgene or to Cas9-derived proteins. Core B will provide animal models and physiologic measurements in the animal models for testing of optimized rAAV vectors, gene editing tools and immune modulation approaches. Program investigators have a track record of interactions and collaborations that we anticipate will continue in future years.

项目总结（总体）