Research

A new gene therapy approach that addresses multiple unmet needs in Parkinson’s in one hit

August 8 2025

While we eagerly anticipate the reporting of results from the recently completed NOPARK trial in Norway (a phase 3 trial of nicotinamide riboside, which is marketed as the supplement Tru Niagen® among other brands), it is worth looking at what other potential treatments for Parkinson’s are coming down the pipeline. Progress may seem painfully slow to those living with this disease, but it is inexorable, and every day brings us closer to better treatments, and ultimately, treatments that can slow, stop or even reverse progression, e.g., a cure. Indeed, it is an exciting time in Parkinson’s research, with 6500 publications mentioning Parkinson’s disease in the title or abstract since the start of the year, within just one publications database (the US National Library of Medicine’s PubMed).

Among these, the functions of two different genetic triggers of Parkinson’s (LRRK2 and PINK1) were recently shown to converge on a neuroprotective pathway in the brain,¹ providing mechanistic support for GDNF therapies already under investigation (convergences like this are exciting because they provide important validation for therapeutic targets). Meanwhile, a new therapeutic target, ACLY (ATP-citrate lyase in case you were interested!), emerged from one of our CEO’s former labs and colleagues in Cambridge, UK. ACLY inhibition rescued Parkinson’s-related pathology in cultured neurons and animal models (zebrafish and mice),² suggesting (supported by a huge volume of experimental data) that ACLY could be a suitable therapeutic target for treating Parkinson’s. Watch this space. But for this research update, we wanted to highlight some more exciting results³ from Jeffrey Kordower, Fredric Mafredsson, and colleagues, with even more immediate translational potential to get treatments into humans living with Parkinson’s disease.

The authors start their paper by highlighting some of the unmet clinical needs in Parkinson’s disease, including the waning efficacy of dopamine replacement therapies over time; the frequent development of levodopa-induced dyskinesias (LID) as an often-debilitating side effect of the gold-standard levodopa therapy; and the ongoing progression of this insidious disease. They then go on to show how their novel gene therapy approach, targeting a type of calcium channel (tiny pores in brain cells that allow for the flow of calcium into and out of neurons), specifically in an affected brain region called the putamen, alleviated all of these problems in a non-human primate (macaque monkeys) model of Parkinson’s. These channels (called voltage-gated Ca_V1.3 calcium channels) have been targeted by Parkinson’s researchers before now based on the observation that their activity has been linked to cellular stress leading to neuronal death in Parkinson’s models. The neurons that are predominantly lost in Parkinson’s project from a region of the brain called the substantia nigra to the putamen, which is where they would normally release the dopamine they make. Loss of dopamine in this region in Parkinson’s (which occurs before the neurons die) leads to dysfunctional activity of Ca_V1.3 channels, which in turn leads to the death of these neurons. Small molecule drugs that block these receptors have been tested in human clinical trials on the basis of promising results from animal studies, but these human trials have failed to date, most likely because these channels are found throughout the body, limiting the dose that can be given owing to peripheral effects.

The big difference in this new study is that, rather than a drug, which is administered peripherally (with effects all over the body), the authors engineered a novel “short-hairpin” RNA designed to turn off or silence these channels. They delivered this shRNA using a harmless, disabled virus (AAV), which was injected directly into the putamen of monkeys with toxin (MPTP)-induced parkinsonism. Effectively, the shRNA is the off switch for these calcium channels that start to play up in Parkinson’s, and the virus is the delivery truck that gets the switch into cells; by injecting the truck and cargo into the putamen, the off switch gets just where you’d want it, and nowhere else. A control group of monkeys underwent the same surgical procedure and also received an AAV virus, but with a scrambled shRNA as opposed to the one targeting Ca_V1.3.

Monkeys that received the Ca_V1.3 shRNA showed reversal of motor deficits even in the absence of any dopaminergic therapy. Their disability scores dropped significantly on the gene therapy, and these improvements were even greater when the gene therapy was combined with levodopa—importantly, the treated group maintained a powerful and significant motor response to levodopa therapy for many months whereas the control group showed a loss of response to levodopa over time, similar to the waning efficacy seen in Parkinson’s patients after a number of years. In other words, the gene therapy made the gold standard levodopa therapy work better and for longer. The gene therapy also almost completely prevented levodopa-induced dyskinesias, a common side effect, which was observed in the control group.

Silencing (turning off) CaV1.3 channels in the putamen also improved balance, gross motor deficits and postural instability relative to the control shRNA, and restored fine motor control and motivation (as seen in a hand reach test). Thus, by switching off these calcium channels in the putamen, the gene therapy off switch directly improved motor function and prevented nasty side effects, two of the three unmet needs introduced above. But rounding out the trifecta of exciting outcomes, the authors also showed that the AAV vector travelled backwards along the axons of neurons to the substantia nigra region, where the off switch rescued dopaminergic neurons that were stressed, but not yet dead, thus protecting these cells and restoring their function and activity.

Collectively, these findings are a massive step forward offering very real, tangible reason for hope, supporting further investigation and clinical development of this approach. There is still more work needed before this new treatment can be tested in humans, but with other, similar gene therapy approaches already in clinical trials, this is hopefully not too far away. If a similar trifecta of positive results is seen in human clinical trials, this clever approach that appears to address several of the unmet clinical needs in Parkinson’s, at least in macaque monkeys, could be ground-breaking for people living with this disease. We look forward to keeping you informed about progress in this space!

1. Bagnoli et al., Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain, PNAS (2025), https://doi.org/10.1073/pnas.2412029122

2. Son et al., Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition, Neuron (2025), https://doi.org/10.1016/j.neuron.2025.03.028

3. Steece-Collier et al., Disease-modifying, multidimensional efficacy of putaminal CaV1.3-shRNA gene therapy in aged parkinsonism male and female macaques, Molecular Therapy (2025), https://doi.org/10.1016/j.ymthe.2025.05.027