SALT LAKE CITY (August 1, 2022) – Halia Therapeutics, a biotechnology company that has used a structure-based drug design strategy to discover a series of small molecule therapeutics targeting important mediators of inflammation, announced today that it will present a poster on the Biological characterization of the therapeutic role of Rab10 modulation in the development of Alzheimer’s disease at the Alzheimer’s Association International Conference 2022 taking place July 31-August 4, 2022 in San Diego, CA.
Details of the poster presentation are as follows:
Monday, August 1, 2022
Theme: Basic Science and Pathogenesis
Abstract: P2-094
Code: 62921
Background:
Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. The continuous genetic research done on this disease demonstrates the vast complexity of the genetic architecture. The most recent whole-genome sequence analysis (GWAS)included 1.1 million individuals and identified 38 loci associated with AD status with seven novel loci. However, there is no reliable therapeutics to combat the late stages of AD as of late. The identified rare variants in the RAB10 gene show protective effects against developing AD. This work demonstrates that inhibition of the expression of Rab10 yields better outcomes in terms of the amyloid-beta ratio and cognition. In addition, we demonstrated that Rab10 modulates the NLRC4 inflammasome complex and their derived products IL-1-beta, IL-18, and TNF-alpha.
Method:
In-vitro experiments were carried out using human neuroblastoma (N2A) cell lines transfected with a mammalian plasmid to overexpress the APP gene and the immortalized microglia HMC3 cell line. We used the compound reference MLi2 and house compounds HT4253 and HT4403 to inhibit the expression of the Rab10. We used ELISA protocols to test the amyloid-beta 40 and 42 ratios, IL-1-beta, IL-18, and TNF-alpha secretion. Western blots immunocytochemistry allowed us to determine the phosphorylation of Rab10 and LRRK2, LAMP1, and ASC. In-vivo behavioral experiments were done using APP/PS1 mice. Hippocampus tissue was collected to run RNA sequence and total proteomics analysis.
Result:
A higher dosage of compound HT4253 and HT4403 inhibits phosphorylation of Rab10 with an IC50 of 82 nM and 63 nM, respectively. The inhibition of Rab10 and LRRK2 activates a higher expression of the LAMP1 protein. The incubation with a high compound dosage improved the secretion of the amyloid-beta 42/40 ratio. The additional experiments and results will be presented at the conference.
Conclusion:
This work provides insights into the protective role of Rab10 against AD and neuroinflammation. Rab10 could be a promising therapeutic target for AD prevention.
Presenting Author:
Josue D Gonzalez Murcia, PhD (Halia Therapeutics)
Authors:
Alexis Mollard, PhD (Halia Therapeutics); David Bearss PhD (Halia Therapeutics)
About Rab10
Rab10 is a member of the RAB family of small GTPases, which are key regulators of vesicular trafficking and are expressed in many cell types. RAB protein functions are tightly controlled, requiring a GDP–GTP exchange that is facilitated by RAB guanine nucleotide exchange factors or GEF. Rab10 is unusual because it is involved in many different cellular functions and has multiple subcellular localizations. Rab10 is expressed in all cell types in the brain and is activated by phosphorylation at Thr73, mediated by LRRK2, a protein kinase associated with Parkinson’s disease. This phosphorylation of Rab10 may also represent a pathologic feature in the brains of AD patients. Increased expression of Rab10 mRNA in the temporal cortex of AD brains has been reported and in vitro studies have shown that targeted knockdown of Rab10 decreased Aβ production, whereas the overexpression of Rab10 increased Aβ production in cultured neuroblastoma cell lines. The importance of Rab10 in the processing of APP and the production of Aβ suggests that targeting Rab10 function may have therapeutic potential. The function of Rab10 in intracellular trafficking and evidence that a reduction of Rab10 results in a decrease in the Aβ42/40 ratio make inhibition of Rab10 an attractive drug target.
About Halia Therapeutics, Inc.
Halia Therapeutics, Inc. is headquartered in Salt Lake City, Utah, and is discovering and developing novel therapeutics to improve the lives of patients with inflammatory disorders and neurological diseases. Halia is advancing innovative medicines that target the immune system’s response to resolve chronic inflammation and eliminate the damage caused by aberrantly activated immune responses. www.haliatherapeutics.com
Company Contact: Andi Groen, Info@haliatherapeutics.com,+1.385.355.4315,
Media Contact: Jessica Yingling, Ph.D., Little Dog Communications Inc.,jessica@litldog.com, +1.858.344.8091