HIV-associated neurocognitive disorders (HAND) continue to be a remarkably prevalent condition in HIV- infected individuals despite the potent effects of combination antiretroviral therapy (cART). The development of HAND represents an important treatment issue for HIV patients that impacts quality of life, mortality, and everyday functioning. Currently, despite 25 years of research, no specific treatments have entered clinical practice for HAND. The overarching aim of this proposal is the development of a novel therapy, intranasal insulin, for HIV-associated neurocognitive disorders (HAND). We have identified this as an innovative, and high potential target based on our preliminary research. HIV-infection and cART are well known to cause alterations in lipid distribution, glucose homeostasis, and energy metabolism that are associated with alterations in insulin signaling. Several decades of research have shown that insulin has multiple actions in brain that regulate many of the same neural pathways perturbed by HIV infection including energy metabolism, lipid metabolism, neurotransmitter channel activity, neurite outgrowth, synaptic strength, and inflammatory signaling suggesting that insulin might protect the CNS in the setting of HIV-infection. In preliminary experiments we found that insulin protected neurons from a broad variety of insults including toxic HIV proteins, as well as ischemic, oxidative, inflammatory, and excitotoxic challenges, in addition to dampening the inflammatory response of microglia. In a novel animal model of HAND produced by infection of conventional mice with a chimeric HIV (EcoHIV) we found that intranasal insulin treatment for 9 days completely reversed cognitive impairment in infected animals. These data are consistent with human studies in healthy volunteers, Alzheimer's and type 2 diabetes patients showing that intranasal insulin improves cognitive function. These preliminary findings strongly suggest that insulin delivered directly to brain may preserve or restore neuronal function in HIV-infected individuals.

Public Health Relevance

HIV-associated neurocognitive disorders (HAND) continues to be a remarkably common condition in HIV-infected individuals despite the potent effects of combination antiretroviral therapy. In this program we propose comprehensive pre-clinical development leading to a clinical trial designed to test a novel therapy for HAND. Our preliminary data suggests that intranasal delivered insulin has neuroprotective, and inflammatory and restorative effects on CNS energy metabolism, suggesting that this therapy may protect the CNS in HIV- infected individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH105280-03
Application #
9282487
Study Section
Special Emphasis Panel (ZMH1-ERB-M (03))
Program Officer
Colosi, Deborah
Project Start
2015-09-01
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$1,379,046
Indirect Cost
$407,988
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Chan, Parco; Saleem, Mahwesh; Herrmann, Nathan et al. (2018) Ceramide Accumulation Is Associated with Declining Verbal Memory in Coronary Artery Disease Patients: An Observational Study. J Alzheimers Dis 64:1235-1246
Nedelcovych, Michael T; Gadiano, Alexandra J; Wu, Ying et al. (2018) Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse. ACS Chem Neurosci 9:809-816
Chaudhuri, Amrita Datta; Dastgheyb, Raha M; Yoo, Seung-Wan et al. (2018) TNF? and IL-1? modify the miRNA cargo of astrocyte shed extracellular vesicles to regulate neurotrophic signaling in neurons. Cell Death Dis 9:363
Nedelcovych, Michael T; Manning, Arena A; Semenova, Svetlana et al. (2017) The Psychiatric Impact of HIV. ACS Chem Neurosci 8:1432-1434
Ubaida-Mohien, Ceereena; Lamberty, Benjamin; Dickens, Alex M et al. (2017) Modifications in acute phase and complement systems predict shifts in cognitive status of HIV-infected patients. AIDS 31:1365-1378
Nedelcovych, Michael T; Tenora, Lukáš; Kim, Boe-Hyun et al. (2017) N-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-l-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders. J Med Chem 60:7186-7198
Nedelcovych, Michael; Dash, Ranjeet P; Tenora, Lukáš et al. (2017) Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its ?-Substituted Ester Prodrugs. Mol Pharm 14:3248-3257
Saleem, Mahwesh; Herrmann, Nathan; Dinoff, Adam et al. (2017) A Lipidomics Approach to Assess the Association Between Plasma Sphingolipids and Verbal Memory Performance in Coronary Artery Disease Patients Undertaking Cardiac Rehabilitation: A C18:0 Signature for Cognitive Response to Exercise. J Alzheimers Dis 60:829-841
Ubaida-Mohien, Ceereena; Lamberty, Benjamin; Dickens, Alex M et al. (2017) Informatic interrogation of CSF proteomic profiles from HIV-infected subjects implicates acute phase and complement systems in shifting cognitive status. AIDS :
Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder - pathogenesis and prospects for treatment. Nat Rev Neurol 12:309

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