EVRYS BIO LLC — Department of Health and Human Services SBIR Phase I: NIAID

Description

DESCRIPTION provided by applicant Reactivation of polyomavirus JCV in the brains of immunosuppressed individuals causes a devastating disease called progressive multifocal leukoencephalopathy PML There are no effective therapies available for PML Although rare the disease carries a andgt fatality rate and patients who survive are severely disabled due to brain damage caused by JCV infection and inflammation Over a million individuals in the U S with acquired immune deficiency syndrome and individuals using immunosuppressive therapies are at risk for PML depending on the underlying immunosuppressed condition up to will develop the disease In particular risk of PML limits the use of certain effective immunosuppressive drugs e g natalizumab adalimumab etanercept and infliximab for treatment of multiple sclerosis MS psoriasis rheumatoid arthritis and Crohnandapos s disease respectively These drugs are counter indicated for patients who are seropositive for JCV up to of healthy adults and of MS patients as example Previous strategies to develop a therapy for PML primarily focused on inhibiting JCV replication Nucleoside analogues such as cytosine arabinoside cidofovir and the anti malarial drug mefloquine are effective in blocking JCV replication in culture but they failed to demonstrate efficacy against PML in the clinic The only treatment option for PML is to restore and allow the immune system to clear the viral infection however this often leads to immune reconstitution inflammatory syndrome IRIS in which increased immune system activity actually increases the damage caused by the infection The present project proposes to validate a novel mechanism of action the activation of a host encoded sirtuin protein by a single molecule that will simultaneously target different cellular sequelae of PML including JCV reactivation and IRIS Sirtuins are NAD dependent deacetylases known for their role in regulating metabolic gene function and the inflammatory response In addition recent studies described herein point to a new role for Sirtuins as broad spectrum viral restriction factors A small molecule screen for sirtuin modulators identified broad spectrum antivirals with nanomolar potency in inhibiting JCV growth in culture The literature predicts the identified sirtuin modulators will also reduce inflammation and importantl one identified scaffold exhibited achievable biodistribution to the brain Brain penetrance minimizes the risk of poor drug availability to the viral and anti inflammatory drug targets of PML The proposed SBIR phase goal is to advance this hit to a lead while validating the hypothesis driven antiviral and anti inflammatory mechanisms of action Confounding past attempts to develop an efficacious PML therapy animal models do not exist for JCV that manifest the infection nor the symptoms of PML in the brain The herein described mechanistic approach as opposed to an antiviral phenotypic approach predicts pharmacodynamic markers to aid in determining a therapeutic window between tolerability and sufficient drug target engagement Such biomarkers will be measured in SBIR phase and downstream to enable successful preclinical and clinical translation In summary a brain penetrant lead that can simultaneously addresses viral infection and inflammatory components of PML represents proof of principle for an innovative technology that addresses the devastating societal need for an effective PML therapeutic PUBLIC HEALTH RELEVANCE Progressive multifocal leukoencephalopathy PML is a devastating disease without a cure It is caused by a virus infection that results in brain dysfunction and often death Immunosuppressed patients are at risk for PML including AIDS patients and those taking effective medications to treat autoimmune diseases such as multiple sclerosis and rheumatoid arthritis FORGE Life Science is developing a drug to treat PML that would save lives and additionally improve the well being of the large population of patients benefitting from antiretroviral and autoimmune therapies by alleviating the risk of fatality caused by PML