A Gene Drive Therapy for HIV: single-administration intervention for high-risk groups

  • Funded by National Institutes of Health (NIH)
  • Total publications:0 publications

Grant number: unknown

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Key facts

  • Disease

    COVID-19
  • Start & end year

    2020
    2025
  • Known Financial Commitments (USD)

    $189,000
  • Funder

    National Institutes of Health (NIH)
  • Principle Investigator

    Pending
  • Research Location

    United States of America, Americas
  • Lead Research Institution

    J. DAVID GLADSTONE INSTITUTES
  • Research Category

    Pathogen: natural history, transmission and diagnostics

  • Research Subcategory

    Immunity

  • Special Interest Tags

    Gender

  • Study Subject

    Non-Clinical

  • Clinical Trial Details

    N/A

  • Broad Policy Alignment

    Pending

  • Age Group

    Unspecified

  • Vulnerable Population

    Drug usersOther

  • Occupations of Interest

    Unspecified

Abstract

PROJECT SUMMARY/ABSTRACTFor COVID-19, persons who inject drugs (PWID) have been identified as a population at high-risk of exposureto SARS-CoV-2 (the virus that causes COVID-19) because of their increased risk of homelessness orincarceration-situations linked to increased rates of the disease transmission and co-infection with HIV-1.Given that a SARS-CoV-2 vaccine is likely 12-24 months away, there is a critical unmet medical need for medicalcountermeasures that could contain COVID-19 outbreaks in the general population and in these difficult-to-reachhigh-risk populations such as PWIDs in particular. Moreover, there is a fundamental gap in our understandingof SARS-CoV-2 infection and pathogenesis in these at-risk PWID populations. Evidence indicates that SARS-CoV-2 infects and depletes T lymphocytes and many HIV-infected PWID have limited access to antiretroviraltherapy and consequently exhibit pre-existing CD4+ T-cell depletion. Hence, SARS-CoV-2 infection couldaccelerate clinical progression to AIDS, or alternatively, SARS-CoV-2 infection in HIV+ PWID could exacerbateCOVID-19 clinical symptoms leading to elevated risk of death. Thus, HIV+ PWID may be at elevated risk ofdeath from SARS-CoV-2 infection. In these PWID populations, reducing T-cell depletion would be highlybeneficial to halting clinical progression and may a viable long-term therapeutic goal. The specific objective ofthis supplement proposal is to repurpose existing technologies to rapidly develop a Gene Drive Therapy (GDT)candidate for SARS-CoV-2 and quantify its breadth of interference and transmission in vitro in patient T-cellsfrom HIV+ PWID. This effort will build heavily off our recent success in engineering an HIV-1 GDT (see ParentAward) and a GDT against Zika Virus (ZIKV), demonstrating that the GDT concept can be repurposed for otherviruses. The central hypothesis-based on extensive preliminary studies in HIV and ZIKV-is that a putativeSARS-CoV-2 GDT, depleted of all the pathogenic viral genes, could target the same cells as wild-type SARSCoV-2 (including T lymphocytes), compete for intracellular resources, and reduce SARS CoV-2 viral load andpathogenesis, thereby serving as a single-administration therapeutic. The rationale for a GDT countermeasurefor SARS CoV-2 is based on extensive data for HIV-1 in humanized mice and positive FDA meetings. We willachieve our objectives via two specific aims: (i) Engineer a SARS-CoV-2 GDT candidate (by adapting the existingBioreactor platform); and (ii) Test the SARS CoV-2 GDT candidate's protective effect on patient T-cells from anHIV+ PWID cohort in Tijuana Mexico. While the GDT approach carries inherent risks, single-administrationtherapeutics would be highly beneficial particularly for treating difficult-to-reach, high-risk PWID populations.Regardless of the success of GDTs in protecting against T-cell depletion, the studies proposed here will havebroad fundamental significance by assaying how SARS-CoV-2 infection impacts T lymphocytes from HIV+PWID. These studies would also provide validation of a novel medical countermeasure with the potential to berapidly deployed against new viral threats.