There are currently no disease-modifying therapies for the treatment of tauopathies, a group of progressive neurodegenerative disorders that are pathologically defined by the presence of tau protein aggregates in the brain.
In Frontotemporal Lobar Degeneration (FTLD), a familial tauopathy, 57 different mutations in the microtubule-associated protein tau (MAPT) gene have been identified. About half of these mutations perturb the finely regulated balance in the splicing of MAPT exon 10, inducing the increase of exon 10-containing splicing isoforms. In turn, this affects the number of microtubule-binding domains present in the mature tau protein, ultimately causing neurodegeneration and tau aggregates.
RNA Therapies are recently gaining their momentum and 12 approved RNA-based drugs have been approved as of today.
We have designed three different RNA-based therapeutical approaches for FTLD, which might be beneficial also for other tauopathies: exon-skipping antisense oligonucleotides (AONs), AAV-vectored antisense chimeric U1 or U7 snRNAs and isoform-specific short interfering RNAs (siRNAs). Via reporter minigenes we have screened several of these molecules. We have validated the efficacy of the best hits for each approach in cultured cells. We are presently performing Proof-of-Concept studies in two orthogonal models of FTLD disease: human iPSc-derived neurons bearing the IVS10+16 mutation and a mouse model bearing the human MAPT gene with the same mutation and recapitulating the disease’s molecular, histopathological and behavioral aspects.
6 Maggio 2022
Michela A. Denti, PhD
Department of Cellular, Computational and Integrative Biology
University of Trento