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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.
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Novartis Institutes for BioMedical Research
Mutations in the LRRK2 gene increase its kinase activity and represent one of the most common genetic causes of Parkinson’s disease (PD). However, preliminary studies with LRRK2 inhibitors in nonhuman primates showed changes in lung morphology and questioned the feasibility of their development for therapy in PD. Baptista and colleagues now show very interesting and encouraging data on different LRRK2 inhibitors and their effects on lung changes in nonhuman primates.
They show convincingly that LRRK2 inhibitors exist that can be used at doses that do not induce lung changes and still inhibit LRRK2 kinase activity in the brain. Furthermore, lung changes were reversible, no functional impairments were detected, and there seems to be a certain safety margin appearing. This data is of utmost importance to the PD research field to encourage further investment into the development of LRRK2 inhibitors as a therapeutic avenue for PD.
The Michael J. Fox Foundation supported this study, and several pharma companies participated in this important effort to find disease-modifying therapies for PD. This incredible collaboration and fruitful teamwork are remarkable and necessary to tackle, and get closer to, a therapy for devastating complex neurodegenerative diseases such as PD. These kinds of collaborative efforts are highly welcome. They greatly serve humankind, and it would be desirable to see more of these endeavors.
View all comments by Derya ShimshekCharité - Universitätsmedizin Berlin
As presented, I am not quite convinced by the findings regarding type II alveolar epithelial cells, and by their interpretation. I’d point out two main points:
1. The quality of the preservation of the content of the lamellar bodies in type II alveolar epithelial cells could be greatly improved. In this paper, it appears poor because of inadequate fixation and processing of samples for electron microscopy. In order to assess lamellar bodies qualitatively and quantitatively, special phospholipid retention protocols have to be used, otherwise the surfactant material is extracted. What one cannot see, one cannot assess.
2. A qualitative analysis is insufficient. To assess the degree of changes, a formal quantitative approach based on stereology, and following the official research policy statement of the ATS/ERS is necessary. This could still be done. It would require adequate representative sampling (systematic uniform random sampling) and measurements (number of alveolar epithelial type II cells per lung and mean size of alveolar epithelial type II cells for assessing hyperplasia/hypertrophy; number of lamellar bodies per alveolar type II cell and mean size of lamellar bodies for assessing intracellular surfactant pool size and distribution; both of these parameters require use of the disector technique).
View all comments by Matthias OchsOttawa Hospital Research Institute
Gain-of-function mutations found in the LRRK2 gene that increase its kinase activity are associated with Parkinson’s disease. Hence, a specific pharmacological inhibition of LRRK2 kinase activity can be an efficient treatment for halting onset and/or development of PD. LRRK2 kinase activity is also responsible for enhanced inflammatory responses to a pro-inflammatory stimulus.
Genetic ablation of LRRK2 kinase activity in murine models of infection does not raise concerns for mounting a proper immune response, suggesting that if there is a way for a specific pharmacological inhibition of LRRK2 kinase activity there should be no weakening of the host immune system.
However, with the COVID-19 pandemic it becomes apparent that any drug that has a potential to cause physiological changes to lungs, even transiently, should be used cautiously—especially in PD patients, who are usually older. Such treatment will likely have to be chronic, if not lifelong. What this will mean for the function of LRRK2 and off-target kinases is not known.
While the report—that the lung tissue effects seen with inhibition of LRRK2 are reversible—is encouraging, effects of a life-long treatment are hardly measurable. Not only in terms of lung physiology, but for normal function of the immune system as well.
Work on inhibition of LRRK2 as a treatment for PD is very promising and I expect it to evolve further, for example drug delivery to the brain only, so we can focus at least on one organ when it comes to side effects of LRRK2 inhibition.
View all comments by Bojan ShutinoskiMake a Comment
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