Molecule therapy effective against Parkinson's disease in rats is also safe for humans

We are inching closer to an effective treatment for Parkinson's disease.
Rupendra Brahambhatt
An illustration of molecule therapywildpixel/iStock

A team of scientists at the Denali Therapeutics research institute in San Francisco has claimed to develop a molecule treatment method for Parkinson’s disease (PD). The molecule therapy can inhibit mutations in LRRK2 (leucine-rich repeat kinase 2 ), a gene linked to lysosomal malfunction and Parkinson’s disease. 

Parkinson’s disease affects over 10 million people across the globe. 60,000 new individuals with PD are discovered in the US alone every year. There is no permanent cure for the condition, and scientists are still unsure what causes it. However, some previously published studies suggest that mutations in the LRRK2 gene are associated with PD progression in humans.

Due to mutations in the LRRK2 gene, the LRRK2 enzyme becomes highly active. It leads to the destruction of lysosomes (membrane-bound subcellular organelles that remove the waste material and performs digestion of macromolecules such as proteins inside human body cells)  and various PD symptoms. Now scientists have created a molecule called DNL201 that can successfully inhibit LRRK2 enzyme activity. They have also tested the molecule on rats, macaques (a monkey species), and human subjects, including 28 patients with PD. 

What is DNL201, and how does it deal with Parkinson’s disease?

Molecule therapy effective against Parkinson's disease in rats is also safe for humans
A diagram depicting LRRK2 inhibition by DNL201 molecule. Source:  P. Lewis, et al., Science Translational Medicine (2022) 

DNL201 is a small molecule capable of getting across the blood-brain barrier. It inhibits LRRK2 activity by decreasing the phosphorylation (the process of linking phosphate group to a molecule to activate or deactivate an enzyme) of “Rab”, the substrate responsible for LRRK2 kinase enzyme activity. The molecule performs target engagement and downstream lysosomal pathway engagement for inhibiting LRRK2 activity and correcting the cellular conditions responsible for PD.

When researchers tested the molecule on rats, they realized that DNL201 was capable of bringing down the activity of LRRK2 kinase. Moreover, the enzyme enhanced lysosomal functions in rat cells. The researchers then ran DN201 trials on macaques for four weeks to check the tolerable dosage levels for primates. After the trials were successful on macaques, the next step was to try DNL201 molecule therapy on humans.

The molecule was tested on a total of 150 human subjects; 28 individuals with PD and 122 volunteers having normal health status. Interestingly, LRRK2 levels in human blood dipped after the introduction of DNL201. Moreover, the subjects didn’t experience any side effects or health issues during the clinical trial.   

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The success of this molecule therapy is of great importance   

Molecule therapy effective against Parkinson's disease in rats is also safe for humans
Source: Matthias Zomer/Pexels

The success of DNL201 as an LRKK2 inhibitor is extraordinary because no current methods attempt to correct cellular level malfunctions that lead to Parkinson’s disease. When asked about the wide-scale implications of this molecule method, lead author and senior medical director at Denali Therapeutics, Danna Jennings, told IE, “the therapeutic goal of treating with LRRK2 inhibitors is to improve lysosomal function and slow the progression of PD. This would be a significant advancement over current treatments for PD, which address only the symptoms.”

She further reveals that lysosomal dysfunction is also related to other neurodegenerative and lysosomal storage diseases such as frontotemporal dementia. So their understanding of lysosomal biology from the DNL201 treatment could also pave the path for treatment for other such diseases as well. “We are applying our expertise in understanding lysosomal biology to develop other types of treatments for other diseases, such as MPS II (Hunter syndrome) and frontotemporal dementia (FTD) caused by mutations in the granulin (GRN) gene,” said Jennings.  

Currently, Jennings and her team are working with Biogen (a biotechnology company that happens to be their strategic partner) on advanced LRKK2 inhibitors that could prove more beneficial to people with PD and can be tested in their following clinical studies. Who knows, maybe their efforts will lead to discovering an effective drug to treat Parkinson’s disease

The study is published in the journal Science Translational Medicine.


Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factors for Parkinson’s disease (PD). Increased LRRK2 kinase activity is thought to impair lysosomal function and may contribute to the pathogenesis of PD. Thus, inhibition of LRRK2 is a potential disease-modifying therapeutic strategy for PD. DNL201 is an investigational, first-in-class, CNS-penetrant, selective, ATP competitive, small-molecule LRRK2 kinase inhibitor. In preclinical models, DNL201 inhibited LRRK2 kinase activity as evidenced by reduced phosphorylation of both LRRK2 at serine-935 (pS935) and Rab10 at threonine-73 (pT73), a direct substrate of LRRK2. Inhibition of LRRK2 by DNL201 demonstrated improved lysosomal function in cellular models of disease, including primary mouse astrocytes and fibroblasts from patients with Gaucher disease. Chronic administration of DNL201 to cynomolgus macaques at pharmacologically relevant doses was not associated with adverse findings. In phase 1 and phase 1b clinical trials in 122 healthy volunteers and in 28 patients with PD, respectively, DNL201 at single and multiple doses inhibited LRRK2 and was well tolerated at doses demonstrating LRRK2 pathway engagement and alteration of downstream lysosomal biomarkers. Robust cerebrospinal fluid penetration of DNL201 was observed in both healthy volunteers and patients with PD. These data support the hypothesis that LRRK2 inhibition has the potential to correct lysosomal dysfunction in patients with PD at doses that are generally safe and well tolerated, warranting further clinical development of LRRK2 inhibitors as a therapeutic modality for PD.