Jennings D, Huntwork-Rodriguez S, Henry AG, Sasaki JC, Meisner R, Diaz D, Solanoy H, Wang X, Negrou E, Bondar VV, Ghosh R, Maloney MT, Propson NE, Zhu Y, Maciuca RD, Harris L, Kay A, LeWitt P, King TA, Kern D, Ellenbogen A, Goodman I, Siderowf A, Aldred J, Omidvar O, Masoud ST, Davis SS, Arguello A, Estrada AA, de Vicente J, Sweeney ZK, Astarita G, Borin MT, Wong BK, Wong H, Nguyen H, Scearce-Levie K, Ho C, Troyer MD. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson's disease. Sci Transl Med. 2022 Jun 8;14(648):eabj2658. PubMed.

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  1. At present, there are no available therapies that can slow the progression of Parkinson’s disease. Pathogenic mutations in the LRRK2 gene increase protein kinase activity and represent the most common genetic risk factor for Parkinson’s disease. Importantly, a large body of work has demonstrated that pharmacological inhibition of LRRK2 can limit the detrimental consequences of mutations across a variety of experimental models. In this study, Jennings et al. share their findings from the first-in-human clinical trials of the LRRK2 kinase inhibitor, DNL201.

    Their preclinical data builds upon previous work linking LRRK2 mutations with lysosomal dysfunction (Eguchi et al., 2018). The authors demonstrate that DNL201 is capable of reversing stress-associated lysosomal enlargements in a cell line expressing the LRRK2 G2019S mutation. Interestingly, the authors expand the scope of their study to investigate fibroblasts derived from Gaucher’s patients carrying GBA1 mutations. Treatment with DNL201 appeared to partially correct dysfunctional lysosomal protein turnover. These findings are consistent with recent data suggesting inhibition of LRRK2 kinase activity can treat lysosomal dysfunction that is not caused by LRRK2-mutations (Sanyal et al., 2020). 

    Their study also examined PBMCs derived from G2019S mutation carriers as well as patients with sporadic PD and healthy controls. Jennings et al. report a roughly twofold increase in pT73 Rab10 in patients with sporadic PD and G2019S mutation carriers alike. It is noteworthy, however, that the primary data, by the way of blots, is absent from this manuscript. Findings surrounding blood-based analysis of Phospho-Rab10 from LRRK2-mutation carriers are mixed. Fan et al. (2021) recently reported elevated Phospho-Rab10 are observed in carriers of the R1441C mutation but not G2019S.

    A promising finding from this study is that DNL201 is well-tolerated in both PD patients and healthy controls. Furthermore, Jennings et al. demonstrate a dose-dependent inhibition of LRRK2 kinase activity (in whole blood). Their data represents an important milestone in the development of the first disease-modifying therapeutic for Parkinson’s disease. A recurring concern from studies of previous LRRK2 inhibitors is the presence of lung pathology in rodents and nonhuman primates (Baptista et al., 2020). Encouragingly, Jennings et al. demonstrate that DNL201 did not appear to have any impact on lung function across all doses investigated during the trial period. As the authors note, longer-term monitoring will be necessary to understand the impact of chronic dosing in follow-up studies. Additional studies are also needed to address target engagement of DNL201 in the human brain and the consequences of LRRK2 kinase inhibition and reversal of disrupted lysosomal functions.

    References:

    Eguchi T, Kuwahara T, Sakurai M, Komori T, Fujimoto T, Ito G, Yoshimura SI, Harada A, Fukuda M, Koike M, Iwatsubo T. LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. Proc Natl Acad Sci U S A. 2018 Sep 12; PubMed.

    Sanyal A, Novis HS, Gasser E, Lin S, LaVoie MJ. LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons. Front Neurosci. 2020;14:442. Epub 2020 May 15 PubMed.

    Fan Y, Nirujogi RS, Garrido A, Ruiz-Martínez J, Bergareche-Yarza A, Mondragón-Rezola E, Vinagre-Aragón A, Croitoru I, Gorostidi Pagola A, Paternain Markinez L, Alcalay R, Hickman RA, Düring J, Gomes S, Pratuseviciute N, Padmanabhan S, Valldeoriola F, Pérez Sisqués L, Malagelada C, Ximelis T, Molina Porcel L, Martí MJ, Tolosa E, Alessi DR, Sammler EM. R1441G but not G2019S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils. Acta Neuropathol. 2021 Sep;142(3):475-494. Epub 2021 Jun 14 PubMed.

    Baptista MA, Merchant K, Barrett T, Bhargava S, Bryce DK, Ellis JM, Estrada AA, Fell MJ, Fiske BK, Fuji RN, Galatsis P, Henry AG, Hill S, Hirst W, Houle C, Kennedy ME, Liu X, Maddess ML, Markgraf C, Mei H, Meier WA, Needle E, Ploch S, Royer C, Rudolph K, Sharma AK, Stepan A, Steyn S, Trost C, Yin Z, Yu H, Wang X, Sherer TB. LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. Sci Transl Med. 2020 Apr 22;12(540) PubMed.

    View all comments by Zhenyu Yue

  2. The findings reported by Jennings et al. represent a comprehensive summary of data so far on DNL201, a leading treatment in development for Parkinson’s disease. Given their pioneering role in moving therapies targeting LRRK2 into clinical testing, Denali and its collaborators should be congratulated for providing this detailed look across both nonclinical and clinical experience with DNL201. Many in the field, including in the patient community, are eagerly watching the progress of these important studies.

    As the authors point out (and as does Lewis in the companion perspective), many questions still remain, and more data will be needed to further assess longer-term safety of LRRK2 inhibitors, along with future readouts on possible efficacy in slowing disease progression. That LRRK2 kinase inhibition may also influence biology linked to other forms of PD associated with GBA1 mutations, as reported by Jennings et al., is intriguing and a topic of emerging interest among the research community.

    At The Michael J. Fox Foundation for Parkinson’s Research, we have made significant investments over the years to drive increased understanding and better measurement of LRRK2 and its cellular substrates and worked closely with Denali and other industry leaders to understand the needs for enabling informative, careful, and scientifically rigorous clinical testing of LRRK2 inhibitors. I am grateful to Denali and all those in the research and drug development communities who are working hard to translate LRRK2 into potentially promising treatments for Parkinson’s disease.

    View all comments by Brian Fiske

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  1. LRRK2 Inhibitor Hits Target, Appears Safe for Parkinson’s

Therapeutics

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