P01HL158506

Models and Gene Therapies for AAT Deficiency - 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. This will allow for the comparison of 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.

University Of Massachusetts Medical School

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Worcester, Massachusetts 016052324 United States

Single Zip Code

NHLBI Program Project Applications (P01 - Clinical Trials Optional) (PAR-18-405)

Amendment Since initial award the total obligations have increased 387% from $2,789,128 to $13,595,317.