Project Portugal 2030

Summary

The central point and novelty of the ARTPD project is to take advantage of RNA interference technologies to downregulate DDC gene expression by specifically target peripheral organs with the highest expression levels of DDC protein and necessarily contribute most to the peripheral decarboxylation of LD in the therapy of PD patients, a technology that we have already used to effectively used to downregulate biological targets associated with disease progression in cancer [25, 26], SARS-CoV-2 [27, 28] and glaucoma [29, 30]. The libraries of short interfering RNA (siRNA) double stranded oligonucleotides will be screened to assess for their ability to downregulated DDC and modulate DDC expression and activity in organs where the enzyme plays a major role, such as the liver and kidney. Additionally, we will evaluate the off-target, cytotoxicity, and the drug-like profile of the best candidates. The outperforming candidate(s), with suitable safety and drug-like profiles, will be selected for in vivo studies in animal models. This proposal is highly innovative for the following reasons: a) drug design strategies for PD have largely overlooked the role of DDC in the disease evolution; b) no anti-DDC siRNA has been developed yet; c) a new class of safe, effective, liver and kidney selective anti-DDC siRNAs can be developed. The ARTPD team has been conducting research in the area of RNA interference (Oligonucleotide chemistry, Pharmacology and Toxicology) for a long time. The current proposal follows the path of previous projects developed in collaboration with Phyzat Biopharmaceuticals Lda (SIRNAC project 33399; SIRNAGLAU Project 39743, SIRNACOVID project 68856), in which the present teams joined e?orts and successfully discovered new leads that act as selective inhibitors of peripheral DDC, the main enzyme involved in LD metabolism in peripheral tissues. The cross-interdisciplinary and complementary backgrounds of the team researchers and consultants will be the driving force and assurance of the project success. The main outcomes of the proposal are the following: a) develop a first-in-class drug candidate that can modulate the excess iron and inflammatory events and regulate DA levels in the brain; b) feed the pipeline with new disease-modifying drug candidates for PD; c) patent the most promising candidates; d) knowledge transfer to pharmaceutical/biotech companies, namely those interested in the field of antiparkinsonians and therapeutic applications thereof; e) train undergraduate and graduate students and early stage researchers; f) disseminate innovative research in international, peer-review scientific journals and international conferences; g) increase the awareness for PD by disseminating our main results to the scientific community and to the society in general. This project fits the current line of research of the applicant and participant/collaborative institutions, which is focused on the drug discovery for neurological disorders. We expect this project to be a step forward in the development of a next-generation of PD drugs to overcome the decreasing therapeutic response of LD and and compensate motor response fluctuations or motor complications, as successfully demonstrated while using the RNA interference technology that we have already demonstrated to effectively downregulate biological targets associated with disease progression in cancer [25, 26], SARS-CoV-2 [27, 28] and glaucoma [29, 30]