R01AI170692

Impact of Gene-Drive Systems for Population Modification on Malaria Vector Mosquitoes - Project Summary

While significant progress has been made in reducing the malaria burden since the turn of the century, the last few years have seen a deceleration of this success. The World Health Organization (WHO) estimates approximately 229 million cases (morbidity) and 409,000 deaths (mortality) in 2019 in its 2020 World Malaria Report. Approximately 95% of the global malaria deaths occurred in only 31 countries, with seven in sub-Saharan Africa accounting for about 51% of all the deaths.

Furthermore, the WHO predicts that there will be no further significant decreases without greater use of existing technologies and the necessary development of new tools. The challenges of the continued demand for new drugs and the slow roll-out of an efficacious vaccine make it urgent to develop new, cost-effective, and efficacious disease-control tools that are safe for people and the environment. This need justifies efforts to develop genetic approaches for controlling malaria parasite transmission.

Long-term, sustainable genetic control will require the deployment of strategies designed to be resilient to the immigration of susceptible mosquitoes and parasite-infected people. Genetically-engineered mosquito strains for population modification have the appropriate performance features for this purpose. Wild mosquitoes immigrating into a region populated by engineered, parasite-resistant mosquitoes will acquire beneficial genes by mating with the local insects. Additionally, persons with malaria moving into the same region will not be able to infect the resident vectors, and therefore are not a source for infection of other people.

We have exploited the molecular mechanisms of CRISPR/Cas biology to develop autonomous gene-drive systems for site-specific, transgene copy number amplification in the mosquito germline. These drive systems carry a cargo of anti-parasite effector genes that prevent transmission of the parasites by the mosquitoes carrying them. The working hypothesis is that these systems will be able to impact transmission dynamics even if they confer a genetic load that impacts reproductive fitness.

We shall investigate the impact of gene-drive system insertions on the recipient mosquitoes to determine effects on reproductive success and drive and effector gene efficacy and stability. Towards these ends, our specific aims are:

1) Evaluate the impact of autonomous gene-drive systems on the reproductive success of Anopheles gambiae ss. and An. coluzzii.
2) Evaluate the multigenerational stability of autonomous gene-drive systems in Anopheles gambiae ss. and An. coluzzii in laboratory cage trials.

The successful completion of these specific aims will inform plans and modeling for the future use of this technology in malaria control.

Irvine University Of California

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Irvine, California 926970001 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 191% from $1,092,110 to $3,173,474.