ATTR is a degenerative, systemic disease characterized by transthyretin fibril deposition in organs like the heart, kidneys, liver, and skin. Patients commonly experience numbness, pain, and muscle weakness in the limbs, which progressively impairs mobility….

eventually requiring wheelchairs or full assistance. Without treatment, it severely reduces quality of life and shortens life expectancy, though newer therapies can slow progression and preserve mobility longer.

The cryoEM work was done by Jun Yu and Xuefeng Zhang in our group at the University of Geneva @UNIGEnews @unige_en @Biologie_UNIGE and data were collected at the Dubochet Center for Imaging (DCI). @DCI_EM.

However, this work has been executed in a very close collaboration with our partners in Bellinzona: Sandra Pinton, Elena Vacchi, Andrea Cavalli, Matteo Pecoraro, and especially Giorgia Melli. @BellinzonaIrb

In our proof-of-concept study we demonstrate that tissue from minimally invasive skin biopsies can be used to characterize fibril composition (such as wild-type to mutant ratios), PTMs, and to determine the three-dimensional structure by cryo-EM.

Fibrils derived from living patients offer the possibility to study filament composition and structure across distinct genotypes, phenotypes and disease stages (fibrils from post-mortem tissue likely reflects the end stages of a disease).

Moreover, skin biopsy can be performed longitudinally, enabling within patient follow-up studies that reveal how amyloid fibrils may evolve over time and in response to disease-modifying intervention.

Patient-derived fibril structures could guide the design of personalized immunotherapies that are more effective and tailored to dominant fibril conformations and epitopes. Therapies could include de novo designed universal binders, such as mini-proteins, peptides or nanobodies.