R01AI167009

In vivo CRISPR engineering of B cells to produce anti-HIV broadly neutralizing antibodies using novel nanoparticles - Project Summary / Abstract.

The quest for an HIV cure remains incomplete, nearly half a century since the onset of the epidemic. Antiretroviral drug cocktails can suppress HIV infection, but suffer in their success owing to side effects and limitations in access and compliance.

Injection of broadly neutralizing antibodies (BNABs) to prevent HIV rebound has had some success, but requires regular re-injection of multiple antibodies to maintain suppression and viral escape. Thus, cost and continued access remain limitations.

Genetic engineering of patient cells has been proposed to overcome all of these shortcomings and could constitute a one-time treatment with lifelong therapeutic value if successful.

In this proposal, we leverage a novel approach developed by Dr. Justin Taylor's laboratory to genetically engineer B cells to express BNABs for the treatment of human immunodeficiency virus (HIV). This strategy has already been used to engineer B cells to produce antibodies protective against influenza virus, respiratory syncytial virus, Epstein-Barr virus, and HIV (Moffett et al., Science Immunology, 2019).

While this approach can ensure protective antibody production, the genetic engineering process required 10 days of complicated ex vivo manufacturing and is not broadly distributable.

To overcome these barriers, we will co-opt a novel, synthetic nanoparticle that was developed in Dr. Jennifer Adair's laboratory to deliver genetic engineering in a single, passive step (Shahbazi et al., Nature Materials, 2019). We show that this nanoparticle can be assembled in less than a day to genetically engineer unstimulated, primary human blood cells and can be modified to specifically interact with target blood cell types in vivo.

Here we will develop this scalable nanoformulation as a vaccine-like in vivo delivery system to direct humoral immunity with multiple BNABs in a clinically-relevant nonhuman primate model of HIV infection. We will use these nanoparticles to directly genetically engineer native primary B cell subtypes and hematopoietic stem and progenitor cells, which can provide lifelong replenishment of antibody-producing B cells.

This research will not only develop a unique toolset against HIV but will provide transformative advances in equitable distribution of gene editing therapies.

University Of Massachusetts Medical School

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.

93.242 - Mental Health Research Grants

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

National Institute of Mental Health (NIMH) [HHS - NIH]

Worcester, Massachusetts 01655 United States

Single Zip Code

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-24-254)

Amendment Since initial award the total obligations have increased 366% from $752,927 to $3,510,912.