TheraSyn

ΔΡΑΣΗ ΕΘΝΙΚΗΣ ΕΜΒΕΛΕΙΑΣ

«ΕΡΕΥΝΩ-ΔΗΜΙΟΥΡΓΩ-ΚΑΙΝΟΤΟΜΩ Β’ ΚΥΚΛΟΣ»|
«ΑΝΤΑΓΩΝΙΣΤΙΚΟΤΗΤΑ, ΕΠΙΧΕΙΡΗΜΑΤΙΚΟΤΗΤΑ & ΚΑΙΝΟΤΟΜΙΑ» (ΕΠΑνΕΚ)|

Ειδική Υπηρεσία Διαχείρισης Επιχειρησιακού Προγράμματος Ανταγωνιστικότητα Επιχειρηματικότητα και Καινοτομία (ΕΥΔ ΕΠΑνΕΚ)

Ειδική Υπηρεσία Διαχείρισης και Εφαρμογής Δράσεων στους τομείς Έρευνας, Τεχνολογικής Ανάπτυξης και Καινοτομίας (ΕΥΔΕ ΕΤΑΚ)

Τίτλος: Νέας γενιάς αντινοηματικά μόρια για θεραπεία της νόσου Πάρκινσον

Title: Next-generation antisense molecules for Parkinson's disease therapy

ΑΚΡΩΝΥΜΙΟ: TheraSyn

ΚΩΔΙΚΟΣ ΕΡΓΟΥ: Τ2ΕΔΚ-01291

PROPOSAL ABSTRACT
Parkinson's disease (PD) is the second most common neurodegenerative disorder and the most common movement disorder with an age of onset at 57. There are approximately 25,000 patients with PD in Greece, of which 5-10% have familial PD that develops before age 50. Classic symptoms include resting tremors, bradykinesia, muscle rigidity, and postural instability. In addition, non-motor symptoms are common and include depression, dementia, pain, sleep problems, bowel and bladder abnormalities, sexual dysfunction, and orthostatic hypotension. PD is not a terminal illness; people can live for 15-25 years from the point of diagnosis, making it a chronic condition. There is no cure, and treatments aim to control and relieve symptoms. Neuropathologically, the cardinal feature is the loss of dopaminergic neurons in the substantia nigra and the appearance of Lewy bodies rich in phosphorylated alpha-synuclein in the remaining neurons. One primary strategy in treating PD is utilizing alpha-synuclein as the therapeutic target. Direct targeting of alpha-synuclein can be achieved by using antibodies that clear the protein from outside neurons, preventing the prion-like spread of pathology into neighboring cells, or by targeting a-synuclein synthesis within cells. Hereby, we have designed and tested antisense oligos (ASOs) that drastically decrease alpha-synuclein levels in cells. Importantly, similar approaches using the same chemical formulation of ASOs have recently received regulatory approval to treat other neurological diseases, and more ASOs are in phase 2 and 3 clinical trials. The objective of this proposal is the development of a drug and companion biomarker for targeted PD therapy. The main goal is to complete the preclinical evaluation of our ASO drugs. The project will be implemented by a consortium formed by three research teams at BRFAA and the Greek companies ProtATonce and e-NIOS, which specialize in drug development and intelligent interpretation of genomic data, respectively.

SUMMARY OF RESULTS
The ASO-based study on Parkinson’s disease (PD), conducted in humanized rats and iPSC neurons from patients with PD, has yielded significant findings. The administration of the lead compound, ASO3, not only reduced monomeric and aggregated alpha-synuclein levels but also increased locomotor activity and enhanced olfactory function in animals, without causing side effects or neurotoxicity. Furthermore, ASO3 restored cytokine expression to wild-type levels, suggesting an immunomodulatory effect. Phosphoprotein multiplexing highlighted the restoration of activated signaling pathways, underscoring the potential of ASO3 in reversing PD pathology. Neurotransmitter measurements indicated subtle shifts toward normalization. Pharmacokinetic analysis of ASO3 revealed that it remained stable in the brains of rats for an extended period. Alongside a comprehensive bioinformatics analysis of RNAseq data, this study has helped assess the mechanisms of action of ASO3 and identify molecular biomarkers of PD. Overall, these results suggest that ASO3 is a promising therapeutic compound for tackling Parkinson’s disease.

PARTNERS
Biomedical Research Foundation of the Academy of Athens (BRFAA)
Protavio
e-NIOS Applications