Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

Abstract

Symptomatic treatments are available for Parkinson’s disease and Alzheimer’s disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration.

Associations between multiple neurological biomarkers and distal sensorimotor polyneuropathy: KORA F4/FF4 study

“…Table 3 provides an overview of these biomarkers and how they could be linked with DSPN. [43][44][45][46][47][48][49][50][51][52][53][54][55] JAM-B and RGMA represent the best candidates for validation given their effects on myelination in other studies. 46,50,53 LAYN and SCARA5 could be relevant given their roles in hyaluronan and iron metabolism, respectively.…”

Blood-based biomarker in Parkinson’s disease: potential for future applications in clinical research and practice

“…However, recently failed anti-alpha-synuclein approaches with cinpanemab and similar results with prasinezumab leave doubts about aSyn as a therapeutic target in PD (Przuntek et al 2004 ; Müller and Kohlhepp 2016 ; Müller et al 2016 ; Jellinger 2019 ; Espay 2022 ). One could postulate that Lewy body pathology with aSyn pathology is not primarily responsible for nigral degeneration in PD (Muller et al 2021; Espay, 2022 ) or that the enrichment of “pathologic” proteins as aSyn, tau or β-amyloid are not specific (Müller et al 2021 ; Espay 2022 ). Concepts of purely aSyn-based biomarker in PD may fall short to address the entire pathophysiology of the disease.…”

“…There are environmental epigenetic influences, such as chronic toxin exposure or still unknown for instance viral or bacterial infections, all of which may serve as further still hypothetical causes for the onset of sporadic PD forms. Therefore, the concept of a more or less singular molecular pathologic biomarker approach is misleading, in particular when it is based on a pathological finding (Müller et al 2021 ).…”

The Pharmacological Potential of Adenosine A2A Receptor Antagonists for Treating Parkinson’s Disease

“…The identification, characterization and classification of adenosine receptors have opened new vistas in pharmacology for treating a wide range of peripheral and central disease states [ 1 , 2 , 3 , 4 , 5 ]. This is particularly true of the potential use of centrally acting adenosine A 2A receptor antagonists for the treatment of neurological and psychiatric illnesses where current therapies provide incomplete symptom relief and where there are no proven strategies that slow or prevent disease progression [ 6 , 7 , 8 , 9 ].…”

“…In particular, adenosine A 2A receptors have a highly selective localization in brain [ 12 ] and are one of the best-characterized GPCRs [ 22 , 23 ]. As discussed in detail below, the selective localization of A 2A receptors to the basal ganglia and the limbic brain region together with their ability to modulate the function of a range of other neurotransmitter systems offers a non-dopaminergic pharmacological approach to the treatment of Parkinson’s disease (PD), and potentially common neuropsychiatric disorders, such as depression and cognitive decline [ 4 , 6 , 9 ]. In addition, the positioning of A 2A receptors on both neurons and glial cells and the ability to modulate pathogenic processes such as excessive glutamate release and the aggregation of toxic protein species identifies them as relevant to providing neuroprotective or disease modifying therapies in a range of neurodegenerative illnesses [ 17 , 20 ].…”