While highly active antiretroviral therapy (HAART) has significantly improved the health of individuals infected with human immunodeficiency virus-1 (HIV), available therapeutics largely target virus replication pathways such that treatment interruption results in the rapid resumption of viral replication and decline of immunologic function. Even despite successful therapeutic control of replication, chronic inflammation, HIV-associated neurocognitive disorders, cardiovascular disease and other comorbidities further threaten the health of an estimated 1.2 million HIV-infected people in the U.S. New therapeutic strategies capable of longer term virus suppression and reductions in the sources of persistent virus would relieve consequences of daily drug compliance and comorbidities for over 34 million HIV-infected people globally. Jericho Sciences? investigational small molecule, FX101, is proposed to target the highly conserved zinc finger domains of lentiviral nucleocapsid (NC) proteins, a well-established therapeutic target for the treatment of HIV. FX101 has demonstrated preclinical safety and antiviral efficacy in multiple in vivo, ex vivo and in vitro models to support continuing translational testing. Zinc finger domains (ZFDs) of HIV nucleocapsid (NC) protein are highly conserved therapeutic targets shared across all lentiviruses, including feline, simian and human immunodeficiency viruses (FIV, SIV and HIV, respectively). Following eight monotherapeutic doses of FX101 over four weeks in chronically FIV-infected cats ? one of the research models for HIV ? blood plasma and cerebrospinal fluid viremia remained 85-95% below corresponding pretreatment levels up to 36 weeks following cessation of treatment, in the absence of observed or measured adverse events (p<0.0005; n=6; one-way ANOVA). These results are unprecedented in FIV-infected cats. Concurrently, integrated provirus in peripheral blood mononuclear cells continued to decrease by 95% from the normalized starting virus load (p<0.0001; n=6; one-way ANOVA). While we have yet to fully elucidate mechanistic implications of the nucleocapsid target profile, the most differentiating feature is the potential long term control of virus production in an apparent systemic reduction of virus replication setpoint. We propose here to conduct translational testing of FX101 in a simian immunodeficiency virus-infected nonhuman primate (SIV/NHP) model to establish the safety profile, therapeutic efficacy, and clinical biomarkers that may implicate this strategic candidate molecule?s potential utility toward a cotherapeutic functional eradication of HIV infection in humans. .
This Phase II SBIR project is designed to translationally test a small molecule candidate intended for therapeutic eradication of HIV-1 infection, in the absence of continuing therapeutic interventions. This work addresses the high priority of next generation HIV therapies with better safety and ease of use, developing and testing HIV treatments that are less toxic, longer acting, have fewer side effects and complications, and easier to take and adhere to than current regimens. In this way, the proposed technology meets NIH?s mission to treat immune-mediated diseases, to develop new and more-effective treatments for HIV-infected people, and to find a cure. Specifically, the technology supports the Trans-NIH Plan for HIV Research to: ? Accelerate the discovery and validation of strategies, targeting new and existing viral and cellular targets that provide safe, tolerable, maximally long-term suppressive antiviral activity. ? ? Advance the discovery and validation of therapeutic strategies to prevent progression of HIV and its associated comorbidities, including inflammation, coinfections, and other clinical complications across the lifespan of HIV-infected individuals. ? Support research on the mechanisms of HIV persistence and develop strategies to prevent the establishment of, decrease, or eliminate viral reservoirs that persist despite optimal antiretroviral (ARV) treatment. ? Develop and evaluate methods, tools, and intervention strategies that improve entry into, and retention in, HIV care. ? Develop and test strategies to improve adherence to ARV drug regimens and regimens to prevent and treat HIV-associated comorbidities used for treatment and prevention in domestic and international settings. Additionally, the proposed technology meets both NIDA?s and NIMH?s Division of AIDS Research priorities to minimize neurotoxicities induced by long-term use of antiretroviral therapy by potentially reducing daily adherence requirements of cART, toward eradication of the virus from HIV-infected individuals to achieve a functional cure.
