APHIOS CORPORATION — Department of Health and Human Services SBIR Phase I: NIAID

Description

PROJECT SUMMARY We hypothesize that Protein Kinase C PKC agonists such as the non tumorigenic Bryoids combined with HDAC inhibitors HDACi represent a valuable pharmacological approach to purge latent HIV from cellular reservoirs We also hypothesize that a combination of a Bryoid and an HDACi co encapsulated in a long circulation pegylated immunonanosomes coated with anti PD L nanobodies will provide efficient HIV latency activation and immunological depletion of latent reservoirs This combination nanosomal approach has the added benefit of concomitantly and significantly reducing systemic toxicities of both PKC and HDACi Our Phase I Specific Aims are construct and characterize nanosomes containing the Bryoid Bryostatin in the lipid membrane and nanosomes of HDAC inhibitors SAHA Romidepsin and Panobinostat in the aqueous core evaluate the cytotoxicity of Bryostatin HDACi and of their corresponding nanosomes in cell culture models and in vivo cytotoxicity and biodistribution in BALB c mouse model to select most efficacious combination and evaluate the synergistic and anti HIV latency antagonistic effects of two nanosomes of different combination of Bryostatin and the alternate HDAC inhibitors in cell culture and in humanized mice models of HIV latency We plan to conduct this Proof of Concept study over a month period with a multidisciplinary team of full time equivalents FTE of an engineer virologist and manufacturing technician Additionally our lean but experienced research team will be advised and supported by Dr Robert F Siliciano Professor of Medicine Johns Hopkins University School of Medicine and Investigator Howard Hughes Medical Institute who will also provide support with respect to the ex vivo evaluation of the combination PKC HDACi nanosomes Dr Eduardo Munoz University of Cordoba Spain an immunologist an HIV latency researcher and Scientific Advisor to Aphios Corporation Dr Santiago Moreno Head Infectious Diseases Ram n y Cajal Hospital and Professor of Infectious Diseases University of Alcal Madrid Spain an HIV clinician and Principal Investigator of an ongoing Phase I IIa clinical trial of Bryostatin for HIV latency in HIV patients on cART and Dr Joseph L Bryant D V M at the Institute of Human Virology University of Maryland Medical School an HIV animal model expert who will lead the in vivo toxicity and efficacy animal studies planned We will establish a Scientific Advisory Review Panel with Drs Siliciano Bryant Munoz and Santiago for the research Should we be successful in achieving our Phase I milestones we will prepare and propose a comprehensive Phase II research and development program which will systematically construct immunonanosomes by coating the most promising nanosomes identified in Phase I anti PD L nanobodies and physically chemically and biologically characterize the immunonanosomes evaluate most potent HIV latency drug combination in an induction activation therapy protocol in the SHIV macaque or alternative model of viral persistence and latency and determine the potential effects of treatment on selected immunological functions during induction therapy The end goal of our research program is to develop a combination therapeutic to clear and free HIV patients from latent viruses curing a chronic disease and reducing the burden of personal toxicities and ending the economic burden of this disease in both developing and developed countries In order to reach these objectives we plan to conduct rigorous clinical studies in a Phase III clinical research program with a commercial partner investor in which we will perform cGMP manufacturing of HIV latency combination therapeutic at the pilot scale level establish a Drug Master File design IND enabling preclinical studies and Phase I II clinical trials prepare pre IND package and establish and conduct pre IND meeting with FDA and file an IND with the FDA We will then conduct Phase I and II clinical trials and license the therapeutic to a multinational pharmaceutical company such as Roche Jandamp J Pfizer Merck or GSK In summary we will utilize Aphios proprietary critical fluid nanosomes CFN process for the formation of small uniform liposomes for the co encapsulation of Bryoids and HDAC inhibitors US Patent Castor and take advantage of promising data we have generated from preliminary studies Perez et al to develop responsive protocols for Phase I and II clinical studies in HIV patients being treated with cART and having a suppressed viral load Guti rrez et al The outcomes of the proposed studies will inform product development for HIV latency and fast track the field to complete elimination of HIV infection and sterilizing cure PROJECT NARRATIVE Currently over million people have died from AIDS and there are over million people living with HIV AIDS worldwide In the United States an estimated million people are currently living with HIV and approximately infections occur each year There is no vaccine against HIV and AIDS if untreated will lead to the death of over of infected individuals years post infection HIV infects several cell types during the course of infection and progression to acquired immune deficiency syndrome AIDS The persistence of latent HIV infected cellular reservoirs represents the major hurdle to virus eradication with anti retroviral therapy ART since latently infected cells remain a permanent source of viral reactivation It has been hypothesized that intensification of ART could reduce the residual viremia but recent studies strongly suggest that this is not the likely scenario Moreover ART is problematic because of long term toxicity drug resistance and the inability to target and eliminate persistent viral reservoirs Therefore other pharmacological approaches targeting the HIV reservoir have been suggested by several investigators as a promising strategy to develop new drugs able to activate latent HIV without inducing global T cell activation We propose to develop a unique combination therapy consisting of a PKC modulator and an HDAC inhibitor to reactivate these latent HIV reservoirs so that HIV can be eliminated by ART and eradicated from the patient s body Our approach has the potential for advancing HIV therapy towards sterilizing cure which currently is out of reach