Maria Rosário Almeida, Ph.D.
i3S Institute of Investigation and Innovation in Medicine
University of Porto
Maria Rosário Almeida graduated in Biochemistry in 1986 at the University of Porto, Portugal. She entered the academic career as assistant and, in parallel, developed a PhD project concerning “Genetic and Biochemical characterization of molecular transthyretin variants” at Centro de Estudos de Paramiloidose at Hospital de Santo António, Porto, Portugal. This research center, created under the leadership of Dr. Corino de Andrade, was specifically dedicated to the study of Familial Amyloidotic Polyneuropathy (FAP), the main form of transthyretin amyloidosis in Portugal. Dr. Almeida concluded the PhD in Biomedical Sciences, specialization in Biochemistry, in 1995, at Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), University of Porto. In 2006 she became Associate Professor of Biochemistry at the Molecular Biology Department at ICBAS, University of Porto and in the last three years she has been director of graduation course (1st cycle) in Biochemistry. Since 1997, her research activities have been developed at the Molecular Neurobiology Group at Instituto de Biologia Molecular e Celular (IBMC) that now also integrates the Instituto de Investigação e Inovação em Saúde (I3S).
Prof. Almeida’s main research interests are the molecular mechanisms and pathophysiology of amyloidosis, in particular, transthyretin amyloidosis. She has been studying structure and function of transthyretin variants and working in in vitro studies of transthyretin aggregation and amyloid fibril formation. In the past few years, her main interest is to search for physiologic and therapeutic modulators of these processes through in vitro and in vivo studies, using FAP mice models. Her research group also investigates the effects of several natural and synthetic compounds as inhibitors of transthyretin amyloidosis and their potential use as therapeutic agents for the disease.
CLR01 and Familial Amyloidotic Polyneuropathy (FAP)
In search for new compounds acting as inhibitors of TTR aggregation and with potential interest for Familial Amyloidotic Polyneuropathy (FAP) therapy, we have been collaborating with the group of Prof. Bitan to test the molecular tweezer CLR01. We started by testing CLR01 as a modulator of TTR aggregation in cell culture and found that CLR01 inhibited TTR oligomerization in the conditioned medium and alleviated TTR induced neurotoxicity.
In addition, we also tested the efficiency of CLR01 activity in vivo in a mouse model of FAP. In this mouse model, which expresses human TTR V30M on a deficient heat shock factor 1 (Hsf- 1) background, TTR aggregates deposit mainly in the gastrointestinal tract and peripheral nervous system. We treated these mice with CLR01 and studied their tissues by immunohistochemistry and western blot analysis. We found that animals treated with CLR01 presented a significant reduction of TTR burden and a concomitant decrease of the associated biomarkers in particular markers of endoplasmic reticulum (ER) stress response, protein oxidation, and apoptosis (Fig. 1). Thus, our pre-clinical data suggest that CLR01 is a promising lead compound for development of innovative, disease modifying therapy for TTR amyloidosis.
Figure 1 – CLR01 decreases TTR burden and associated toxicity in the stomach and nervous system of hTTR V30M/HSF mice. Immunohistochemistry analysis of TTR in stomach and dorsal root ganglia (DRG) of mice treated with CLR01 (right panels) and age-matched controls (left panels) (representative images); 20× magnification. Bar graphs: quantification of immunohistochemistry images is represented as percentage of occupied area ± SD (**p < 0.01; ***p < 0.005).