New genetic therapies target Parkinson's progression

George Ransley and Anthony Schapira from University College London published a major review examining how genetic therapies are being tested to slow the progression of Parkinson's. While medications like levodopa and surgical options like Deep Brain Stimulation have transformed daily symptom management since the 1960s, a treatment that halts the underlying condition has remained out of reach. That landscape is shifting as scientists move away from a one size fits all approach and towards precision medicine. Scientists have now linked over 100 different genetic areas to Parkinson's. Having a family history of the condition is known for around 15 to 25 percent of people, and between 15 and 20 percent carry identifiable genetic risk variants. By studying what these genes actually do inside our cells, researchers have uncovered two major trouble spots: the cell's recycling centres, known as lysosomes, and the cell's power stations, known as mitochondria. Designing treatments to fix these specific biological hiccups is the main focus of modern clinical trials, and many of these therapies could end up helping people with and without these specific genetic variations. Fixing the cell's recycling centre with GBA1 Changes in the GBA1 gene are the most common genetic risk factor for Parkinson's. How common this is varies around the world, showing up in 10 to 15 percent of European people with the condition, up to 20 percent of Ashkenazi Jewish people, 7 to 8 percent of Chinese people, and up to 50 percent in West African populations for certain variants. Carrying a GBA1 variant does not guarantee someone will develop the condition, as only 10 to 20 percent of carriers ever do. However, when people with a GBA1 variant do develop Parkinson's, it often starts at a younger age and can progress faster, bringing more challenges with thinking and memory alongside movement symptoms. The GBA1 gene holds the recipe for an enzyme called GCase, which lives inside the cell's recycling centre and breaks down fatty waste. When the gene is faulty, this enzyme gets stuck and cannot do its job properly, allowing waste and a sticky protein called alpha synuclein to build up. Fascinatingly, sluggish GCase activity is also seen in people with Parkinson's who do not have a GBA1 mutation, meaning treatments aimed at boosting this enzyme could have wide reaching benefits. The frontrunner in this area is ambroxol, a humble medicine used safely as a cough syrup since the 1870s. Researchers discovered that ambroxol acts like a molecular escort, latching onto the sluggish GCase enzyme and guiding it safely into the cell's recycling centre so it can get to work. After a smaller initial study showed that ambroxol successfully reaches the brain and boosts GCase levels by 35 percent, a massive Phase 3 trial called AsProPD is now underway involving 330 people both with and without GBA1 mutations, with results expected in 2029. A smaller Phase 2 trial called AMBITIOUS is also looking specifically at whether ambroxol can protect memory and thinking skills in 65 people with GBA1 variants, with results due in the coming year. Other ambroxol trials are actively running in Australia, the Netherlands, and Israel. Beyond cough medicine, scientists are testing new designer molecules called allosteric activators that bind to the GCase enzyme to supercharge its activity. While one drug called pariceract recently had its trial halted because it was not effective enough, others like GT02287 and VQ101 are showing positive early safety results in human trials. Researchers are even testing ways to use focused ultrasound with tiny microbubbles to temporarily open the protective barrier around the brain to deliver fresh GCase enzyme directly where it is needed, alongside gene therapy trials like PROPEL, which uses a harmless virus to deliver a healthy copy of the GBA1 gene straight into the fluid surrounding the brain. Turning down the volume on LRRK2 While GBA1 problems are caused by an enzyme doing too little, variations in a gene called LRRK2 cause the exact opposite problem by making an enzyme work in overdrive. LRRK2 mutations are found in about 1 to 2 percent of people with Parkinson's overall, though they are much more common in North African Arab, Ashkenazi Jewish, and Portuguese communities. People with LRRK2 variations generally experience a milder form of the condition, with slower progression, fewer non movement symptoms, and a very good response to standard levodopa medication. Remarkably, in the rare cases where someone carries both a GBA1 and a LRRK2 variant, their condition behaves more like the milder LRRK2 version, suggesting it might even have a protective effect. Because the LRRK2 protein is hyperactive, and is also found to be overactive in some people who do not even carry the gene variant, the goal here is to calm it down. Pharmaceutical companies have developed small molecule inhibitors to act like a dimmer switch. One leading drug, BIIB122, was tested in a large trial called LUMA in people with early stage Parkinson's with and without the gene variant. While it successfully calmed the enzyme down, it did not slow down symptoms enough in the broader group, so the company stopped testing it in people without the gene variant. However, they are continuing the BEACON trial specifically for people who carry the LRRK2 mutation, with results expected in 2027. Another similar dimmer switch drug, NEU411, has just entered a Phase 2 trial called NEULARK for people with early LRRK2 Parkinson's. Recharging the cell's batteries with PINK1 and Parkin Every cell relies on tiny battery packs called mitochondria to generate energy, and keeping them healthy is vital for brain cells. Two genes, PINK1 and PRKN, work together as a quality control team to spot damaged battery packs and clear them out. When someone inherits faulty copies of these genes from both parents, it often leads to early onset Parkinson's before the age of 50. PRKN variations are the most common genetic cause of early onset Parkinson's worldwide. Like LRRK2, this form of the condition tends to progress slowly, responds well to levodopa, and rarely causes memory problems, though people can be more prone to involuntary movements known as dyskinesias. Researchers are looking at several ways to help this quality control team do its job. A new drug called MTX115325 is currently in Phase 1 human trials; it works by blocking an enzyme that normally puts the brakes on mitochondrial cleanup, effectively letting the cell clear out damaged batteries much faster. Scientists have also looked at repurposing cancer drugs known as cAbl inhibitors, which were thought to protect the Parkin cleanup crew from oxidative stress. This path has been bumpy, as prominent drugs like nilotinib failed to show benefit and another called vodobatinib actually worsened markers of nerve injury. However, two related drugs, radotinib and risvodetinib, are still being tested, with Phase 2 results for radotinib expected in early 2027. Clearing out the clumps with SNCA The SNCA gene was the very first gene ever linked to Parkinson's. It provides the instructions for making alpha synuclein, the protein that misfolds and clumps together inside brain cells in almost everyone with the condition, regardless of their genetics. Stopping this protein from clumping and spreading from cell to cell is one of the biggest targets in research today. One major approach is passive immunisation, where people are given infusions of laboratory made antibodies designed to mop up the sticky protein. While one antibody called cinpanemab was stopped after failing to show an impact, another called prasinezumab is showing promise. Although its initial trials did not hit their main targets, deeper analysis suggested that it might be slowing down movement progression, particularly in people taking levodopa. This has sparked a huge Phase 3 trial called PARAISO, which will report its findings by 2031. An even cleverer approach is active immunisation, which uses a vaccine to train a person's own immune system to make antibodies against the sticky protein. This is cheaper to produce and requires fewer hospital visits. A vaccine now known as AC7104.056 showed in early trials that it could cut levels of toxic protein clumps in the spinal fluid by half, and it is now in a Phase 2 trial called VacSYn with results due in 2028. Another vaccine, UB312, is also moving forward in early trials after showing it can safely lower alpha synuclein levels. Other teams are testing ways to stop the cells from dying in response to the protein clumps, such as the drug KM819 which is currently in Phase 2 trials. What genetics mean for treatment today While we wait for these trial results to roll in over the next few years, knowing a person's genetic makeup is already starting to help doctors tailor existing treatments. Because people with LRRK2 variations respond so well to levodopa, and those with PRKN variations are more likely to experience dyskinesias, doctors can adjust medication doses more thoughtfully. For those with GBA1 variations, where memory and thinking can be more vulnerable in later stages, doctors are advised to be cautious when prescribing dopamine agonists. There was previously some debate about whether Deep Brain Stimulation surgery might speed up cognitive changes in people with GBA1 variants, but recent long term studies have reassuringly shown that this is not the case. There is still no licensed medication on the pharmacy shelves that slows down Parkinson's, and several prominent trials have fallen short along the way. Yet the sheer number of targeted therapies moving into late stage human testing between now and 2032 shows that understanding the genetics of the condition has given scientists their clearest roadmap yet.