Methods of treating HIV-associated neurological disorders (HAND)

Inventors

HE, Johnny • Zhao, Xiaojie

Assignees

Rosalind Franklin University of Medicine and Science

Abstract

In the present disclosure, doxycycline-inducible astrocyte-specific HIV Tat transgenic mice (iTat), a surrogate HAND model, were treated with PNU-125096, a positive allosteric modulator of α7 nicotinic acetylcholine receptor (α7 nAChR) and effects on Tat-induced behavioral impairments and neuropathologies were observed. This disclosure shows that PNU-125096 treatment significantly improved locomotor, learning and memory deficits of iTat mice while inhibited glial activation and increased PSD-95 expression in the cortex and hippocampus of iTat mice. α7 nAChR knockout eliminated the protective effects of PNU-125096 on iTat mice. In addition, inhibition of p38 phosphorylation by SB239063, a p38 MAPK-specific inhibitor, exacerbated Tat neurotoxicity in iTat mice. These findings demonstrated for the first time that α7 nAChR activation led to protection against HAND and suggest that α7 nAChR and PNU-125096 hold significant promise for development of therapeutics for HAND.

Core Innovation

The invention provides methods of treating HIV-associated neurological disorders (HAND) in a subject by administering an effective dose of a positive allosteric modulator (PAM) of α7 nicotinic acetylcholine receptor (α7 nAChR), such as PNU-120596, optionally in conjunction with an integrase inhibitor and/or other antiretroviral agents. Experimental evidence demonstrated that such treatment significantly improved locomotor activity, learning and memory deficits, and reduced glial activation and neuronal injury in a surrogate HAND model utilizing doxycycline-inducible astrocyte-specific HIV Tat transgenic mice (iTat).

The problem addressed by this invention is the lack of effective treatment options for HAND, which remains prevalent even in the era of combination antiretroviral therapy (cART). Current antiretrovirals used in cART regimens have limited penetrance into the central nervous system and have not shown effective results in treating HAND. HIV viral protein Tat is a major contributor to HAND pathogenesis, causing astrocyte and microglia activation, chronic neuroinflammation, and deteriorating neuronal integrity, leading to behavioral and cognitive impairments.

Through studies involving both in vivo and in vitro models, the activation of α7 nAChR via positive allosteric modulators was shown to provide neuroprotection against Tat-induced behavioral and neuropathological impairments in iTat mice. The neuroprotective effects were absent in α7 nAChR knockout mice, demonstrating the specificity of the mechanism. Furthermore, the findings implicate the involvement of the p38 MAPK signaling pathway and the postsynaptic density protein PSD-95 in mediating the neuroprotective actions, suggesting that α7 nAChR and specific PAMs like PNU-120596 represent promising therapeutic candidates for HAND.

Claims Coverage

The patent contains one independent claim which defines the core inventive method, with further dependent claims specifying details and alternatives.

The main inventive feature is the therapeutic combination of a specific α7 nAChR PAM, PNU-120596, and an integrase inhibitor for treating HAND, as outlined in the sole independent claim. Dependent claims further detail dosing, additional antiretrovirals, and expected clinical benefits.

Stated Advantages

Documented Applications