Can cell and gene therapies improve cognitive symptoms in Parkinson’s disease?

Abstract

Advanced therapeutic medicinal products (ATMPs), including cell and gene therapies, are in development for Parkinson's disease (PD). In many cases, the goal is to replace the lost dopamine (DA), which is anticipated to improve motor dysfunctions associated with DA loss. However, it is less clear the extent to which these therapeutic interventions may impact on the wide range of cognitive symptoms that manifest as the disease progresses. Although the accepted perception is that cognitive symptoms are predominately non-DAergic in origin, in this commentary, it is argued that several, specific cognitive processes, such as habit formation, working memory and reward processing, have been reported to be DA-dependent. Furthermore, there is evidence of DAergic medications modulating these behaviours in PD patients. Finally, the potential for cell and gene ATMPs to influence these symptoms is considered. It is concluded that DA replacement through ATMPs is likely to improve certain DA-dependent symptoms, but only sparse clinical data are currently available and the ability to precisely titrate DA transmission is likely to be complex.

Defining the unknowns for cell therapies in Parkinson's disease

“…The mesocortical dopaminergic circuit, which comprises the head of the caudate nucleus, rostral putamen, intermediate zone of subthalamic nucleus and the dorsolateral prefrontal cortex, is involved in higher cognitive, or executive, functions, whereas the mesolimbic dopaminergic circuit, which comprises the nucleus accumbens, ventromedial striatum, rostral ventral, ventromedial subthalamic nucleus and anterior cingulate cortex, is involved in reward processing and apathy/depression ( Hirano, 2021 ; Lelos, 2022 ; Meder et al, 2019 ). Disruption to the mesolimbic and mesocortical pathways in people with PD is consistent with PET imaging data that suggest reduced dopamine transmission in ventral striatal/nucleus accumbens regions and cingulate/prefrontal cortical areas.…”

“…Given that dopamine is associated with some aspects of cognitive and neuropsychiatric dysfunction in PD, it is reasonable to consider whether cell therapies may be capable of alleviating these symptoms ( Lelos et al, 2012 ; Lelos, 2022 ). Consistent with this hypothesis, work in rodent models of PD has shown that human and rodent foetal dopamine grafts can improve cognitive processing, visuospatial dysfunction and reward/motivational impairments ( Heuer et al, 2013a , b ; Lelos et al, 2016 ).…”