Purging Latent HIV Reservoirs through a Combination HIV Therapeutic

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