P1, N=64, Recruiting, 1ST Biotherapeutics, Inc. | Not yet recruiting --> Recruiting | Trial primary completion date: Sep 2024 --> Dec 2024

P2, N=150, Not yet recruiting, Neuron23 Inc.

P2, N=50, Recruiting, Denali Therapeutics Inc. | Not yet recruiting --> Recruiting

Since PAK6 binds LRRK2 via its GTPase/Roc-COR domain and the R1441C mutation is located in the Roc domain, we used microscale thermophoresis and AlphaFold2-based computational analysis to demonstrate that PD mutations in LRRK2 affecting the Roc-COR structure substantially decrease PAK6 affinity, providing a rationale for the differential protective effect of PAK6 toward the distinct forms of mutant LRRK2. Altogether, our study discloses a novel role of PAK6 in ciliogenesis and points to PAK6 as the first LRRK2 modifier with PD mutation-specificity.

P1, N=17, Completed, D. Western Therapeutics Institute, Inc. | Recruiting --> Completed

P1, N=16, Recruiting, D. Western Therapeutics Institute, Inc. | Not yet recruiting --> Recruiting

P2, N=50, Not yet recruiting, Denali Therapeutics Inc.

P2, N=201, Completed, D. Western Therapeutics Institute, Inc. | Trial primary completion date: Dec 2025 --> Aug 2024 | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> Aug 2024

P1, N=80, Recruiting, Halia Therapeutics, Inc. | Not yet recruiting --> Recruiting

P1, N=16, Not yet recruiting, D. Western Therapeutics Institute, Inc.

P1, N=82, Completed, Biogen | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Aug 2024 | Trial primary completion date: Dec 2024 --> Aug 2024

Our findings conducted an integrated bioinformatic analysis to develop a CAFs-related miRNAs model that provides prognostic insights into individualized and precise treatment for prostate adenocarcinoma patients. Downregulation of miR-106b-5p in CAFs significantly suppressed tumor growth, suggesting a potential therapeutic target for cancer treatment.

P1, N=80, Not yet recruiting, Halia Therapeutics, Inc.

P2, N=200, Active, not recruiting, D. Western Therapeutics Institute, Inc. | Recruiting --> Active, not recruiting

These effects were curtailed by the selective ALK inhibitors NPV-TAE684 and alectinib. LPA enhanced the inhibitory phosphorylation of the tumor suppressor FoxO3a, and this response was impaired by the ALK inhibitors. These results indicate that LPA stimulates mitogenesis of human neuroblastoma cells through a crosstalk with ALK.

P1, N=18, Completed, Biogen | Active, not recruiting --> Completed

P1, N=147, Completed, Neuron23 Inc. | Recruiting --> Completed

The results showed that Mn induced cytotoxicity, oxidative stress, and tumor necrosis factor-α production, which were attenuated by an LRRK2 inhibitor, GSK2578215A...Furthermore, E2 attenuated the Mn-induced Sp1 expression by decreasing the expression of Sp1 via the promotion of the ubiquitin-dependent degradation pathway, which was accompanied by increased protein levels of RING finger protein 4, the E3-ligase of Sp1, Sp1 ubiquitination, and SUMOylation. Taken together, our novel findings suggest that Sp1 serves as a critical TF in Mn-induced LRRK2 expression as well as in the protection afforded by E2 against Mn toxicity through reduction of LRRK2 expression in microglia.

Consequently, the regulation of the dopamine synthesis pathway was affected in N27 cells, thereby leading to altered levels of tyrosine hydroxylase, dopamine transporter, Nurr1, and dopamine release. Overall, the G2019S LRRK2 mutation disrupted astrocyte function, thereby aggravating PD progression.

Notably, GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice. Taken together, our findings offer experimental evidence indicating that the gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, suggesting LRRK2 as a potential therapeutic target in colon cancer patients exhibiting hyper LRRK2 kinase activity.

We propose that LRRK2 plays a significant role in regulating the stemness of GSCs and that suppression of LRRK2 kinase activity leads to reduced GBM malignancy and proliferation. In the near future, targeting LRRK2 in patients with high LRRK2-expressing GBM could offer a superior therapeutic strategy and potentially replace current clinical treatment methods.

P1, N=18, Active, not recruiting, Biogen | Recruiting --> Active, not recruiting

P1, N=81, Active, not recruiting, Biogen | Recruiting --> Active, not recruiting

P1, N=147, Recruiting, Neuron23 Inc. | N=64 --> 147 | Trial completion date: Feb 2024 --> Jul 2024 | Trial primary completion date: Feb 2024 --> May 2024

P1, N=15, Recruiting, Biogen | Not yet recruiting --> Recruiting

NIACIN, TAE-684, ROCILETINIB, and others treat ccRCC. We found ccRCC prognostic genes that work. This discovery may lead to new ccRCC treatments.

P2, N=640, Recruiting, Biogen | Trial completion date: Aug 2025 --> Dec 2025 | Trial primary completion date: Aug 2025 --> Dec 2025

P1, N=15, Not yet recruiting, Biogen

P2, N=200, Recruiting, D. Western Therapeutics Institute, Inc. | Phase classification: P2b --> P2

For the first time, a small molecule with LRRK2 inhibition properties presented (re)myelinating properties in primary OPCs cultures and potentially in the in vivo murine model. This study provides an in vivo proof of concept for a LRRK2 inhibitor, confirming its potential for the treatment of MS.

P1, N=82, Recruiting, Biogen | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=640, Recruiting, Biogen | Phase classification: P2b --> P2

What's more, LRRK2 regulated TLR4/NF-κB signaling pathways and NLRP3 inflammasome, and TLR4/NF-κB pathways was involved in the molecular mechanism of LRRK2 on lung cancer cells. In conclusion, this study suggested that the mechanism of si-LRRK2 inhibiting the progression of lung cancer is to regulate the TLR4/NF-κB signaling pathways and NLRP3 inflammasome.

The effect appears lysosomal specific as LRRK2 inhibition did not affect cell death induced by a variety of other cell death inducers that did not directly affect lysosomes. In addition, data on the mechanisms underlying LRRK2 inhibitor modulation of lysosomal damage will be shown - including lysotracker-based measurement of lysosomal integrity, RNAseq analysis of transcriptional footprints, and knockdown of key genes.

Moreover, 12-month-old G2019S KI mice exhibited a more prolonged hypokinetic response to systemic SCH-23390 compared to wild-type mice. We conclude that G2019S KI mice show age-dependent enhancement of endogenous D1 transmission in the striatum.

P1, N=40, Terminated, Neuron23 Inc. | N=64 --> 40 | Trial completion date: Sep 2023 --> Jun 2023 | Active, not recruiting --> Terminated; Business decision

Notably, these manifestations were more obvious with simultaneous knockdown of LINC00707 and miR-382-5p compared with knockdown of LINC00707 alone. LINC00707 is overexpressed in SKOV3 cells and promotes SKOV3 cell proliferation and resistance to chemotherapeutic drugs via targeting the miR-382-5p/LRRK2 axis.

Furthermore, Nrf2 activator, sulforaphane, ameliorated cypermethrin-induced mitochondrial impairment and oxidative stress and provided protection against dopaminergic neuronal death. The findings indicate that DJ-1 and LRRK2 independently alter Nrf2-mediated changes and a complex interplay among DJ-1, LRRK2, and Nrf2 exists in the regulation of mitochondrial function in cypermethrin-induced Parkinsonism.

Deletion or mutation of LRRK2's Rab38 binding site in the N-terminal armadillo domain decreases LRRK2 membrane association, pericentriolar recruitment, and ability to phosphorylate Rab10. In sum, our data identify Rab38 as a physiologic regulator of LRRK2 function and lend support to a model in which LRRK2 plays a central role in Rab GTPase coordination of vesicular trafficking.

The PI3K pathway mutation status could be considered as a potential biomarker to predict better immunotherapeutic efficacy and clinical outcomes after immunotherapy in HNSC patients.

The half-maximal inhibitory concentration (IC50) results obtained with the cohort from TCGA showed that Z-VAD-FMK (Caspase inhibitor), S-Triphenylmethyl-L-cysteine (S-Trityl-L-cysteine), and TAE684 (ALK inhibitor) had higher IC50 values in low-expression patient (p < 0.05). SLC7A11 overexpression is associated with favorable prognosis of patients with UCEC and is associated with TIICs and the responses to immunotherapy.