It is commonly accepted that Parkinson's disease results from the loss of dopamine neurons in the substantia nigra in the midbrain, but the underlying cause of this loss is largely unknown. Parkinson's disease is most often treated with the precursor dopamine. levodopa (L-Dopa) or a dopamine receptor agonist.
However, these drugs lack specificity due to the wide distribution of dopamine receptors in the brain and peripheral organs which contribute to the disruption of other dopaminergic systems leading to many serious side effects. Thus, new precision therapies for Parkinson's disease allowing selective modulation of circuits affected by Parkinson's disease are highly sought after.
In this study, scientists developed a gene therapy to treat the main symptoms of Parkinson's disease in non-human primates. As humans are primates, there is a significant probability that this approach could be applied to humans, whereas research using animals more distant from humans, such as mice, is very often not transferable to humans.
The approach they developed takes advantage of a highly innovative strategy that does not require significant genetic modification and therefore has high potential for clinical applications in humans (Source: university of Toronto via Wikipedia)
Cellular receptors are a kind of molecular valves on the surface of cells that are controlled by certain signals (for example insulin to bring glucose into cells). A way of modifying the behavior of a cell, more natural than modifying its genome, therefore consists of acting on the signal controlling the receptor.
The researchers are using a very particular technique in this study: They are using cell receptors activated only by a synthetic ligand (RASSL) or a synthetic receptor activated exclusively by synthetic drugs (DREADD). This currently state-of-the-art technology is used in biomedical research, particularly in neuroscience, to manipulate the activity of neurons.
RASSL and DREADD are families of G protein-coupled receptors (GPCRs). These gene therapy-modified receptors do not respond to endogenous ligands, but can be activated by nanomolar concentrations of pharmacologically inert small molecules. There are several types of these receptors, derived from muscarinic or κ-opioid receptors. One of the first DREADDs was based on the human muscarinic M3 (hM3) receptor.
The innovative approach described in this article can precisely modulate the direct blood glucose pathway without affecting other dopamine pathways and can likely prevent the occurrence of many L-Dopa-induced side effects.
Additionally, for L-Dopa administration to be effective, it requires the survival of at least some nigral dopamine neurons to convert it to dopamine, which contributes to the decline in its effectiveness after long-term use in patients. parkinsonians. The method described here, in contrast, does not require the survival of nigral dopamine neurons and may provide a treatment option for advanced non-human primate patients who have lost most or all of their nigral dopamine neurons. To give an image, it's as if they had grafted new receptors on other neurons than the ones that are dying.
The article is very comprehensive and probably the key point for Parkinson's patients is that this approach was able to reverse Parkinson's symptoms in Parkinson's primates after 8 months of treatment.
Another key feature of this approach is its significantly extended window of effectiveness compared to a standard 6-hour window for L-Dopa. This new method is effective 24 hours after drug administration in Parkinson's monkeys and shows no signs of downtime during the extended therapeutic window.
In addition, benefits are to be expected in terms of improvement in depression which often affects Parkinson's patients. Not only, the precision gene therapy approach that scientists have developed has the potential to transform the treatment landscape for Parkinson's disease, but it can be adapted and may be adapted to other brain disorders.