LM11A-31 Safety and Tolerability in Aging People Living With HIV and Neurocognitive Impairment

As people with HIV (PWH) age, the effects of chronic viral infection and associated inflammation put them at higher risk for central nervous system (CNS) complications, including neurocognitive impairment (NCI). Up to half of PWH have some form of NCI, leading to impaired daily functioning, reduced medical access, and lower quality of life. In addition to the effects of HIV, evidence indicates that PWH are at risk for other age-related degenerative diseases such as Alzheimer's disease (AD)-related pathology. In the normal brain, proteins called neurotrophins protect the brain and support the development and stabilization of memories. An important modulator of the neurotrophins, nerve growth factor (NGF) and Brain Derived Neurotrophic Factor (BDNF), is the p75 neurotrophin receptor (p75NTR). This receptor can enhance pro-growth, pro-survival processes or cause degeneration and death of unfit neurons through an interaction with neurotrophin precursors, proneurotrophins. During development, the balance of mature versus proneurotrophin signaling is used to eliminate poorly connected neurons (low neurotrophin/high p75NTR signaling). In the healthy brain, expression of p75NTR is suppressed and pro-growth, pro-survival processes dominate through the actions of NGF and BDNF. However, when neurons are stressed by disease, damage and inflammation, the precursors to NGF (proNGF) and BDNF (proBDNF) increase indicating reduced availability of the beneficial mature neurotrophins. Under these conditions, p75NTR increases, engages with the pro-neurotrophins and supports degenerative processes. Inflammation is often one of the first indicators of disease and is responsible for a variety of early neuronal changes that impair function and set the stage for disease. When HIV virions or gp120, interact with macrophages or microglia in the brain they induce the secretion of factors into the medium that alter neural function beginning with a chronic destabilization of intracellular calcium, cytoskeletal modifications and increases in the p75NTR. Studies indicate that the small molecule, p75NTR ligand, LM11A-31, interacts with the p75NTR to shift the balance of neurotrophin activity and inflammation from degeneration to neuroprotective and anti-inflammatory activity that can protect against HIV-associated neurodegeneration. By intervening and stabilizing neural function as pathological processes begin to develop, LM11A-31 has the potential to provide an effective disease-modifying intervention for PWH. Since the actions are expected to suppress disease activity, the intent is to modify the course of disease before the development of more permanent damage. Participants who show early signs of cognitive decline are therefore the best candidates for treatment. To assess the therapeutic potential of LM11A-31, the proposed trial will evaluate safety and tolerability in participants with mild cognitive decline and collect preliminary neurocognitive and biomarker data to evaluate the neuroprotective and anti-inflammatory effects in PWH.