The Role of Precision Medicine in Parkinson Disease

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Precision medicine offers a promising therapeutic strategy for patients with Parkinson disease, allowing for tailored treatments which reflect the unique pathophysiology in each patient.

Precision medicine, also known as personalized or individualized medicine with the tailoring of specific treatments to the right person at the right time, may be a promising therapeutic strategy for Parkinson disease (PD). A review published in the Journal of Neurology summarizes the clinical trials which target genetic forms of PD, the available data on mechanisms of action, challenges related to therapeutic trials, and the benefits of precision medicine.

Precision medicine requires combining data on specific important biomarkers, along with a patient’s medical history and other health-related factors, to form a targeted prevention and treatment plan. The possible benefits of precision medicine include diagnosing disease at an earlier stage, identifying the optimal treatment option, maintaining patient safety, improving treatment quality and health system efficacy, and moving beyond reactive approaches to preventing damage (ie, protection of neurons to avoid neuronal death).

As the pathophysiology of PD may differ in each patient, precision medicine may play an important role in PD, allowing for tailored treatments which reflect the unique pathophysiology of the disease. Many studies published in the last decade have significantly contributed to the understanding of the genetic architecture of PD. Researchers have identified many Mendelian loci known to cause familial PD, as well as common loci that are mostly associated with a small increase in risk for PD. Interestingly, alterations in the same gene may lead to different variants and mutations with different risk associations for PD.

A better understanding of the pathophysiology allows for precision medicine and the development of treatments based on mechanism of the disease, with the aim of modifying the disease course rather than just targeting symptoms. The researchers present a review of clinical trials which target genetic forms of PD.

Parkinsonism Associated With GBA Mutations

Mutations in the glucocerebrosidase (GBA) gene, a known cause of Gaucher disease, are a common risk for PD and are present in up to 10% of PD patients worldwide.  There are >300 mutations in the GBA gene and the clinical presentation of PD may vary from a mild to a more severe form. A high prevalence of these mutations has been documented among Ashkenazi Jews and those from the Netherlands, while these mutations are less common among Norwegian PD patients.

While it is not fully understood how GBA leads to the development of PD, targeted treatments can be directed towards the modulation of gylcosphingolipid turnover and restoration of enzyme function.

Treatment can be directed at preventing substrate accumulation through the modulation of gylcosphingolipid turnover. Positive results from the phase I study MOVES-PD have reported a dose-dependent decrease in cerebrospinal fluid glucosylceramide levels with the use of the glycosylsynthase inhibitor Venglustat; a phase II study is currently ongoing.

Treatment can also be directed at restoration of enzyme function, resulting in an increase in glucocerebrosidase activity, especially in the brain. These options include enzyme-replacement therapy (ERT), gene therapy, or early glucocerebrosidase chaperones:

·   ERT = while ERT with recombinant glucocerebrosidase is available for Gaucher disease, there are no data available on the use of ERT in PD.

·   Gene Therapy = gene therapy using adeno-associated virus-mediated expression of glucocerebrosidase had positive results in pre-clinical studies for GBA and Prevail Therapeutics, a new company launched in 2017, is expected to publish the results of a clinical trial in 16 GBA-PD patients.

·   Early glucocerebrosidase chaperones = several early glucocerebrosidase chaperones were previously investigated. While isofagomine had no significant clinical improvement for patients with Gaucher disease, ambroxol is a promising agent that was shown to improve lysosomal function and increase enzyme activity. Ambroxol is currently being studied in the AiM-PD trial, which includes GBA-positive and GBA-negative PD patients, and may also be relevant to patients with idiopathic PD. LTI-291, an activator of the GCase enzyme, showed a dose-dependent brain penetration in a phase 1b trial that included patients with GBA-PD.

Small molecules can also be used to treat PD by modifying GBA-independent pathways. In oncology cell cultures, RTB101, an inhibitor of target of rapamycin complex 1 (TORC1), reduced the levels of glucosylceramide, the main substrate of GCase. A phase 1b/2a is of RTB101 with sirolimus is currently ongoing and includes PD patients with and without GBA mutations.

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LRRK2‑Associated Parkinsonism

Similar to GBA, mutations in LRRK2 are more common in certain ethnicities and they are the most common cause of autosomal dominant PD. Some point mutations in LRRK2 are causative for PD, while coding polymorphisms in the gene are strong risk factors. Additional higher frequency variants at the LRRK2 locus may contribute to a small increase in the risk for developing PD. The mechanisms by which mutations cause PD are not completely understood, but it appears to result from increased LRRK2 kinase function, supporting the potential benefit of kinase inhibitors.

While there has been improvement in the potency, selectivity and brain penetrance of LRRK2 inhibitors, efficacy and safety remain a concern. Several structurally different LRRK2 inhibitors from Genentech, GSK, Merck and Pfizer are in the pipeline. Biogen is currently recruiting LRRK2 patients into a phase 1 trial to assess a single intrathecal injection of the compound BIIB094, an antisense oligomere.

Major Challenges

Precision medicine trials are more complicated than standard clinical trials, and must overcome several challenges; these include, but are not limited to, the need for a large number of study participants and the need for genotyping a larger proportion of patients with PD. The relative lack of biomarkers that reflect disease progression and response to treatment is another major challenge.

The lead author of this review, Professor Susanne Schneider from the Ludwig Maximilians University in Munich, Germany, is convinced that a new era of research for Parkinson therapy is beginning. She told us that “recruitment of studies will take the genetic makeup of patients and their individual clinical phenotype into account. The idea is to have the study cohort as homogenous as possible so that effects can stand out and are not lost in the fog. This may also allow to keep numbers of participants much smaller. Prof Schneider also noted that, “stricter inclusion criteria will make recruitment more difficult at the same time, as fewer patients will be eligible.”

“Notably, patients are more and more involved in early phases of trial planning and patients feel they are part of the process – and are thus more willing to participate in trials. These are exciting times!” she remarked.

The review authors concluded that “advancing precision medicine will further encourage and support the next generation of scientists to develop creative new approaches for detecting, measuring, and analyzing a wide range of biomedical information—including molecular, genomic, cellular, clinical, behavioral, physiological, and environmental parameters.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Schneider SA, Alcalay RN. Precision medicine in Parkinson’s disease: emerging treatments for genetic Parkinson’s disease. J Neurol. 2020;267(3):860–869. doi:10.1007/s00415-020-09705-7