TAT-TrkB

Objetivo temático: The present project has the following objectives: 1) Evaluation of in vivo ADMET profile and of in vivo efficacy of TAT-TrkB; 2) Validation of TrkB-ICD to monitor TAT-TrkB therapeutic efficacy (Companion diagnostic tool); and 3) Validate the efficacy of TAT-TrkB in AD patient-derived brain organoid model.

Área Científica: Neurology

Síntese do Projeto: The brain-derived neurotrophic factor (BDNF) and its receptor, TrkB-FL, comprise one of the most important endogenous neuroprotective systems, pivotal for cognitive function. We found that amyloid-beta peptide (Aβ) promotes the cleavage of TrkB-FL, through a calpain-mediated mechanism, giving rise to new fragments: a truncated receptor (TrkB-T’) and an intracellular fragment (TrkB ICD). This cleavage has a tremendous impact, as it decreases TrkB-FL levels, thus compromising cognition, alongside producing biological active fragments. In particular, TrkB-ICD accumulates in the nucleus where it affects gene expression, displays tyrosine kinase activity, and, when overexpressed in the hippocampus of mice, it impairs learning and memory. Importantly, we evaluated TrkB-FL cleavage in post-mortem brain samples from AD patients and we observed an increase of TrkB-ICD levels with AD progression. Moreover, the analysis of TrkB ICD levels in cerebrospinal fluid (CSF) from AD patients revealed to be significantly higher when compared to aged matched non-AD individuals. Remarkably, we developed a new compound, TAT-TrkB, capable of crossing the blood-brain barrier and prevent TrkB-FL cleavage while recovering BDNF actions in vitro, ex vivo and in vivo (pilot study). Now, pharmacokinetics, toxicity and efficacy studies are mandatory to confirm the therapeutic potential of this novel compound. Additionally, the evaluation of TrkB-ICD in CSF and in blood will be performed to understand if it would allow to monitor TAT-TrkB therapeutic intervention. Importantly, to overcome problems of extrapolating animal to human results, which has been a major bottleneck in the drug discovery process, efficacy of TAT-TrkB in human-derived hippocampal organoids will be assessed.

Investigador Responsável na UC: Bruno Manadas

Unidade Orgânica UC: CNC - Reitoria

Instituições participantes no Projeto:

• Universidade de Coimbra;
• Associação da Faculdade de Farmácia para a Investigação e Desenvolvimento;
• Universidade da Beira Interior,
• Faculdade de Engenharia da Universidade do Porto;
• Associação para Investigação e Desenvolvimento da Faculdade de Medicina;
• Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento.

Instituição Financiadora/Gestora: Santa Casa da Misericórdia de Lisboa (SCML)

Programa de Financiamento: SCML - Prémio Mantero Belard 2021

Período de execução: 20/06/2022 - 19/06/2022 (36 meses)

Custo total elegível (EUR): 199.560,00

Técnico do Projeto: Kayleigh Mikaela Oliveira Rodrigues (kayleigh.rodrigues@uc.pt)

Contacto: 239247021