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Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.

ABSTRACT: The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC9492778 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.

Jiang Ying Y Alam John J JJ Gomperts Stephen N SN Maruff Paul P Lemstra Afina W AW Germann Ursula A UA Stavrides Philip H PH Darji Sandipkumar S Malampati Sandeep S Peddy James J Bleiwas Cynthia C Pawlik Monika M Pensalfini Anna A Yang Dun-Sheng DS Subbanna Shivakumar S Basavarajappa Balapal S BS Smiley John F JF Gardner Amanda A Blackburn Kelly K Chu Hui-May HM Prins Niels D ND Teunissen Charlotte E CE Harrison John E JE Scheltens Philip P Nixon Ralph A RA

Nature communications 20220921 1

The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbe ...[more]

PMID: 36130946

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Project description:ObjectivesDegeneration of the cholinergic basal forebrain nuclei (CBFN) system has been studied extensively in Alzheimer's disease (AD). White matter hyperintensities are a hallmark of aging as well as a common co-morbidity of AD, but their contribution to CBFN degeneration has remained unclear. Therefore, we explored the influence of white matter hyperintensities within cholinergic subcortical-cortical projection pathways on CBFN volumes and regional gray matter volumes in AD and age- and gender-matched controls.MethodsWe analyzed magnetic resonance images (MRI) from 42 patients with AD and 87 age- and gender-matched control subjects. We assessed the white matter hyperintensity burden within the cholinergic projection pathways using the Cholinergic Pathways Hyperintensities Scale (CHIPS), and applied probabilistic anatomical maps for the analysis of CBFN volumes, i.e. the Ch1-3 compartment and the Ch4 cell group (nucleus basalis of Meynert), by diffeomorphic anatomical registration using exponentiated lie algebra analysis of voxel-based morphometry. Using multiple linear regression analyses, we explored correlations between regional gray matter volumes and the extent of white matter hyperintensities or CBFN volumes in both groups.ResultsIn AD, all CBFN volumes were significantly smaller than in controls, and white matter hyperintensity burden within the cholinergic projection pathways was not correlated with CBFN volume. In controls, white matter hyperintensity burden within the cholinergic projection pathways was inversely correlated with CBFN volume when corrected for sex and total intracranial volume, but this correlation was no longer significant after correction for age. Voxel-wise multiple linear regression analyses using threshold-free cluster enhancement revealed that in controls, cholinergic pathway hyperintensities correlated with gray matter loss in perisylvian areas, whereas the were no effects in AD. Moreover, we found that CBFN volumes correlated with distinct regional cortical atrophy patterns in both groups.ConclusionOur results indicate that white matter hyperintensities and AD pathology contribute independently but additively to the degeneration of cholinergic basal forebrain structures. Whereas AD is primarily associated with CBFN volume loss, cholinergic degeneration associated with white matter hyperintensities appears to involve disruption of cholinergic cortical projection fibers with less pronounced effects on CBFN volumes.

Project description:BackgroundGait disturbance is an early, disabling feature of Parkinson's disease (PD) that is typically refractory to dopaminergic medication. The cortical cholinergic system, originating in the nucleus basalis of Meynert of the basal forebrain, has been implicated. However, it is not known if degeneration in this region relates to a worsening of disease-specific gait impairment.ObjectiveTo evaluate associations between sub-regional cholinergic basal forebrain volumes and longitudinal progression of gait impairment in PD.Methods99 PD participants and 47 control participants completed gait assessments via an instrumented walkway during 2 minutes of continuous walking, at baseline and for up to 3 years, from which 16 spatiotemporal characteristics were derived. Sub-regional cholinergic basal forebrain volumes were measured at baseline via MRI and a regional map derived from post-mortem histology. Univariate analyses evaluated cross-sectional associations between sub-regional volumes and gait. Linear mixed-effects models assessed whether volumes predicted longitudinal gait changes.ResultsThere were no cross-sectional, age-independent relationships between sub-regional volumes and gait. However, nucleus basalis of Meynert volumes predicted longitudinal gait changes unique to PD. Specifically, smaller nucleus basalis of Meynert volume predicted increasing step time variability (P = 0.019) and shortening swing time (P = 0.015); smaller posterior nucleus portions predicted shortening step length (P = 0.007) and increasing step time variability (P = 0.041).ConclusionsThis is the first study to demonstrate that degeneration of the cortical cholinergic system predicts longitudinal progression of gait impairments in PD. Measures of this degeneration may therefore provide a novel biomarker for identifying future mobility loss and falls. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dataset Information

Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.

Publications

Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.

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