Vés al contingut

M Mar Mañu Pereira

Cap del laboratori de recerca en anèmies minoritàries - Investigadora sènior Directora científica de la ERN-EuroBloodNet Coordinadora de les plataformes europees de registre de pacients en hematologia ENROL i en anèmies minortàries RADeep

Institucions de les que formen part

Investigador postdoctoral
Càncer i malalties hematològiques infantils
Vall Hebron Institut de Recerca
Cap del laboratori de recerca en anèmies minoritàries del VHIR 2018 - actualitat
Institut de Recerca contra la Leucèmia Josep Carreras - 2016-2018
Institut d'Investigacions Biomèdiques August Pi i Sunyer / Hospital Clínic de Barcelona - 2002-2016
Doctora en BioMedicina 2009

Línies de recerca

Laboratory of Rare Anemia Disorders

RESEARCH LINE: RARE ANEMIA DISORDERS


Principal Investigator

María del Mar Mañú Pereira, PhD

 

Research Team

Amira Idrizovic, MSc, PhD Researcher

Valeria Rizzuto, MSc, PhD Researcher

Anna Collado Gimbert, MD, Postgraduate Researcher

Victoria Gutierrez Valle, MSc, Postgraduate Researcher

María de los Ángeles Rodríguez, PhD, Project Manager

Claire Diot Lefebvre, MA, Project Manager


BACKGROUND

Rare anemia disorders (RADs) embrace a highly heterogeneous group of red blood cell and erythropoiesis defects characterized by presenting anemia of variable degree, from mild to life threatening chronic blood-transfusion dependence conditions. RADs include mainly sickle cell disorders (SCD), Thalassemia disorders, Rare constitutional hemolytic anemia due to a red cell membrane anomaly or to an enzyme disorder, Constitutional dyserythropoietic anemia and Constitutional anemia due to iron metabolism disorders.


Despite the rapid developments in genetic testing and the subsequent increased knowledge of molecular defects underlying RADs, disease pathophysiology and complex genotype-phenotype correlations are poorly understood and often unexplained. The recent availability of new therapeutic options for RADs makes even more crucial the development of innovative diagnostic strategies for patients’ genetic and phenotypic characterization for development of predictive scores and personalized medicine. Thus, novel diagnostic, exploratory and functional tests are needed in order to identify new disease mechanisms, to discover novel biomarkers, to improve disease classification, and to investigate differences in response to therapy.


Genetic and genome-wide association studies have found that two factors influence the SCD clinical expression: the ability of the patient to produce HbF and the co-existence with alpha-thalassemia but, it is unlikely they are the only ones. Through the new techniques of massive sequencing and association studies, genes with potentially effects to the pathogenesis of SCD or modulators of the phenotype disease have become candidates for study. These genetics modulators can be divided in; Primary: responsible of HbS polymerization and RBCs sickling and Secondary: modulators of sub phenotypes and complications of the disease. Predicting the phenotype of SCD in the first months of life, or even in the adult life, would allow a precise prognosis, individualized treatment and avoid unnecessary interventions. However, it is necessary to correlate these new variants with the physiological behavior of the RBCs and certain clinical manifestations allowing the definition of markers that prevent the appearance of acute events or predict the response to treatments.


The Lorrca® Maxsis is a unique instrument which combines RBC deformability by ektacytometry, osmoscan, oxygenscan and aggregometry; all temperature controlled. It is capable of fully automated measurement and calculation of various phenomena of RBC’s by analysis of their rheological behavior. The technique accurately detects deformability as a function of shear stress, as a function of oxygen tension (pO2) and aggregation of the RBCs respectively.


Additionally, the future of medicine aims to bioengineer devices to mimic human systems to predict efficiently for different patients (personalized medicine) in a fast way. They also may provide new approaches to develop novel dynamic disease models. A step forward in this field concerns "organ-on-chip" technologies. By integrating living cells cultures in microfluidic devices, the most relevant biological and mechanical properties of organic functional units can be reproduced.


However, as for other rare diseases, basic, translational and clinical research in RADs is hampered by the existing fragmentation or unavailability of comparable data at the EU level. A European approach for the standardised collection of data regarding the main clinical complications of RADs is fundamental to establish the need and the priorities in the development of research projects, clinical trials, guidelines and health policies that allow the better provision of healthcare to RADs patients.


RESEARCH STRATEGY AND SCOPE

Our research strategy is focused on the development and validation of innovative methodological approaches for better characterization of patients affected by RADs according to their individual features to allow personal risk profiles and personalized medicine.

Specific objectives include:

1)        To investigate and / or validate genetic modifiers of RADs both new and previously described by GWAS as markers for prognosis and clinical course based on massive sequencing approaches.

2)        To assess the RBC rheological properties by use of ektacytometer LoRRca and the two available modules: Osmoscan and Oxygenscan. The results will provide information of RADs patients risk profile and response to treatment.

3)        In collaboration with IBEC, to model the progression of RADs in a spleen-like filtering unit using microfluidic technologies to develop a novel diagnostic device for prognosis and patients’ stratification. This device will be used for the characterization under flow of rheological and mechanical properties of single RBCs.

4)        To develop AI-algorithms combining different –OMICs data (genomics, metabolomics) with other laboratory and clinical data for personalized medicine in RADs.


In parallel, we are one of the three coordinating hubs of the European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet), established in 2017 to contribute to innovative, efficient and sustainable health systems and facilitate access to better and safer healthcare for EU citizens while decreasing the cross-border health barriers existing for information and patient mobility in rare hematological diseases (RHDs).


On the specific area of the epidemiological surveillance, we are coordinating the establishment of the European Rare Blood Disorders Platform (ENROL), conceived in the core of ERN-EuroBloodNet and with the endorsement of European Hematology Association, as an umbrella for both new and already existing registries on RHDs. ENROL aims at avoiding fragmentation of data by promoting the standards for patient registries' interoperability released by the EU RD platform, combining the exhaustiveness of data collection at EU level for health planning and epidemiological porpoises, with a higher level of data granularity for identification of patients’ cohorts.


In this context, we are also coordinating the implementation of the Rare Anaemia Disorders European Epidemiological Platform (RADeep), contributing to ENROL on the field of RADs. RADeep was endorsed by ERN-EuroBloodNet for the standardized collection of data of patients affected by any RADs at the European level. RADeep is built in line with the EU RD Platform, and is open to any national registry and medical center willing to actively collaborate as data providers in EU, starting with a pilot in 7 European countries: Belgium, Denmark, France, Germany, Italy, Spain and Sweden.


ONGOING COMPETITIVE PROJECTS


ERN-EuroBloodNet – CHAFEA - EU4H-2022-ERN-IBA. ‘European Reference Network on Rare Hematological Disorders’. Coordinador: Pierre Fenaux (AP-HP, Paris). PI: María del Mar Mañú Pereira. Duration: March 2022 – September 2023.

Summary: The European Reference Network in Rare Hematological Disorders, ERN-EuroBloodNet, was officially established by the European Commission in March 2017 as one of the 24 ERNs in rare disorders. ERN-EuroBloodNet is conceived to contribute to innovative, efficient and sustainable health systems and facilitate access to better and safer healthcare for EU citizens while decreasing the cross-border health barriers existing for information, samples and patient mobility in Rare Hematological Diseases (RHD). www.eurobloodnet.eu


GA 964908 — ERICA — H2020-SC1-BHC-2018-2020. ‘European Rare dIsease research Coordination and support Action’. Coordinator: Franz Schaefer (University of Heidelberg, Germany). PI: María del Mar Mañú Pereira. Duration: March 2021 – February 2025

Summary: ERICA consortium aims to build on the strength of the 24 individual European Reference Networks (ERNs) in Rare Diseases and create a platform that integrates all ERN’s research and innovation capacity. Through knowledge sharing, engagement with stakeholders in the rare disease domain and assembly of transdisciplinary research groups working across the global health spectrum ERICA strives to reach the following goals: new intra- and inter-ERN rare disease competitive networks; effective data collection strategies; better patient involvement; enhanced quality and impact of clinical trials; increased awareness of ERN’s innovation potential; Through integration of ERN research activities, outreach to European research infrastructures to synergistically increase impact and innovation ERICA will strengthen the research and innovation capacity of the ERNs. This will result in safe, accessible and efficient access of therapies for the benefit of patients suffering from rare diseases and conditions.


GA 101017549 – GENOMED4ALL - H2020-SC1-FA-DTS-2020-1. ‘Genomics and Personalized Medicine for all though Artificial Intelligence in Haematological Diseases’. Coordinator: Federico Álvarez (Universidad Politécnica de Madrid, Spain). PI: María del Mar Mañú Pereira. Duration: January 2021 – December 2024

Summary: GENOMED4ALL will support the pooling of genomic, clinical data and other “-omics” health data through a secure and privacy respectful cross-border data sharing platform based on the novel Federated Learning scheme, to advance research in personalised medicine in haematological diseases thanks to novel AI models. GENOMED4ALL will make use of the existing infrastructures, including powerful High Performance Computing facilities, hospital registries, data processing tools, and pre-existing repositories, starting from 10 clinical partners repositories to be enlarged especially by the resources provided by ERN-EuroBloodNet where GENOMED4ALL clinical partners have a leading position. GENOMED4ALL will demonstrate the potential and benefits of trustable and explainable AI technologies, with a novel approach to AI models and algorithms to exploit the powerful set of "-omics" data which will be at researchers' disposal leading to more reliable and meaningful outcomes for advancing research and personalised medicine, with 3 use cases covering oncological and non-oncological Haematological Diseases, including: Myelodysplastic syndromes, Multiple Myeloma, and Sickle Cell Disease.


PI20/01454 – INTEGRA - AES – ISCiii. ‘Enabling personalized medicine of sickle cell disease patients based on integrative diagnosis of new generation methodologies’. PI: María del Mar Mañú Pereira. Duration: January 2021 – December 2023.

Summary: Sickle cell disease (SCD) is a rare life threating condition with an increasing health burden in Spain. Hematologic stem cells transplantation is the only curative treatment, usually indicated before the severity of the clinical picture is still unclear; meanwhile gene therapy is still on clinical research. New therapeutic options (i.e Crizanlizumab, Voxelotor) arise a new challenge in SCD; prognosis and personalized medicine become increasingly more important. INTEGRA aims to develop an integrative diagnostic approach based on deep phenotypic and genetic characterization through combining new generation methodologies. Red blood cells sickling behavior will be evaluated by the newly invented Oxygenscan ektacytometry to assess changes in parameters linked to SCD physiological and genetic modulators evaluated through GWAS approach. INTEGRA-SCD will translate into clinical practice the results of genomics, phenotypic characterization and clinical data combined in a single approach resulting on a reliable stratification of SCD patients for personalized medicine.


GA947670 – ENROL - CHAFEA — 3HP- HP-PJ-2019. ‘European Rare Blood Disorders Platform’. Coordinator: María del Mar Mañú Pereira. Duration: June 2020 – May 2023.

Summary: ENROL has been conceived in the core of ERN-EuroBloodNet as an umbrella for both new and already existing registries on rare hematological disorders (RHDs). ENROL aims at avoiding fragmentation of data by promoting the standards for patient registries’ interoperability released by the EU RD platform. ENROL’s principle is to maximize public benefit from data on RHDs opened-up through the platform with the only restriction needed to guarantee patient rights and confidentiality, in agreement with EU regulations for crossborder sharing of personal data. Accordingly, ENROL will map at the EU level demographics, survival rates, diagnosis methods, genetic information, main clinical manifestations and treatments in order to obtain epidemiological figures and identify trial cohorts for basic and clinical research. Moreover, it will allow promoting research especially for those issues that remain unanswered or sub optimally addressed by the scientific community and promoting clinical trials for new drugs. ENROL will enable the generation of evidence for better healthcare for RHD patients in EU as ultimate goal.


GA 860436 – EVIDENCE - H2020-MSCA-ITN-2019. ‘Erythrocytes Properties And Viability In Dependence Of Flow And Extra-Cellular Environment’. Coordinador: Lars Kaestner (Universität des Saarlandes, Germany). Principal Investigator: María del Mar Mañú Pereira. Duration: October 2019 – September 2023.

Summary: The objective of EVIDENCE is the exploration of the properties and behaviour of RBCs under flow conditions and in vivo to understand pathophysiology and to design novel diagnostic devices. Theoretical models will help to understand these RBC properties and will enable the transfer of the gained knowledge into diagnostic devises in general and into the development of a spleen-on-the-chip in particular. Furthermore, we aim to understand the effect of the flow in bioreactors, allowing the efficient production of RBCs in vitro with the goal to produce RBC for transfusion.



SELECTED PUBLICATIONS


Moraleda C, Aguilar R, Quintó L, Nhampossa T, Renom M, Nhabomba A, Ruperez M, Aponte JJ, Achtman AH, Mañú Pereira MDM, Schofield L, Alonso PL, Macete E, Menéndez C. Pathophysiology of Anemia in HIV-Infected Children Exposed to Malaria. Am J Trop Med Hyg. 2021 Jan 18;104(3):1003-1012


Rizzuto V, Mencattini A, Álvarez-González B, Di Giuseppe D, Martinelli E, Beneitez-Pastor D, Mañú-Pereira MDM, Lopez-Martinez MJ, Samitier J. Combining microfluidics with machine learning algorithms for RBC classification in rare hereditary hemolytic anemia. Sci Rep. 2021 Jun 30;11(1):13553.


Kountouris P, Stephanou C, Archer N, Bonifazi F, Giannuzzi V, Kuo KHM, Maggio A, Makani J, Mañú-Pereira MDM, Michailidou K, Nkya S, Nnodu OE, Trompeter S, Tshilolo L, Wonkam A, Zilfalil BA, Inusa BPD, Kleanthous M; on behalf of the International Hemoglobinopathy Research Network (INHERENT). The International Hemoglobinopathy Research Network (INHERENT): An international initiative to study the role of genetic modifiers in hemoglobinopathies. Am J Hematol. 2021 Nov 1;96(11):E416-E420.


Rizzuto V, Koopmann TT, Blanco-Álvarez A, Tazón-Vega B, Idrizovic A, Díaz de Heredia C, Del Orbe R, Pampliega MV, Velasco P, Beneitez D, Santen GWE, Waisfisz Q, Elting M, Smiers FJW, de Pagter AJ, Kerkhoffs J-LH, Harteveld CL and Mañú-Pereira MdM (2021) Usefulness of NGS for Diagnosis of Dominant Beta-Thalassemia and Unstable Hemoglobinopathies in Five Clinical Cases. Front. Physiol. 2021 Volume 12.


Hanny Al-Samkari, M.D, Eduard J. van Beers, M.D., Ph.D, Kevin H.M. Kuo, M.D., Wilma Barcellini, M.D, Paola Bianchi, Ph.D, Andreas Glenthøj, M.D., Ph.D, María del Mar Mañú Pereira, Ph.D., Richard van Wijk, Ph.D., Bertil Glader, M.D., Ph.D, and Rachael F. Grace, M.D. The Manifestations of Disease in Pyruvate Kinase Deficiency: Report from the Pyruvate Kinase Deficiency Burden of Disease International Working Group. Haematologica 2020 Volume 105(9):2229-2239


Huisjes R, Makhro A, Llaudet-Planas E, Hertz L, Petkova-Kirova P, Verhagen LP, Pignatelli S, Rab MA, Schiffelers RM, Seiler E, van Solinge WW, Vives Corrons JL, Mañú-Pereira M, Kaestner L, Bogdanova A, van Wijk R. Density, heterogeneity and deformability of red cells as markers of clinical severity in hereditary spherocytosis. Haematologica. 2020 Jan 31;105(2):338-347


Bianchi P, Fermo E, Glader B, Kanno H, Agarwal A, Barcellini W, Eber S, Hoyer JD, Kuter DJ, Maia TM, Mañu-Pereira MDM, Kalfa TA, Pissard S, Segovia JC, van Beers, Gallagher PG, Rees DC, van Wijk R; with the endorsement of EuroBloodNet, the European Reference Network in Rare Hematological Diseases. Addressing the diagnostic gaps in pyruvate kinase deficiency: Consensus recommendations on the diagnosis of pyruvate kinase deficiency. Am J Hematol. 2019 Jan;94(1):149-161.

                         

Llaudet-Planas E, Vives-Corrons JL, Rizzuto V, Gómez-Ramírez P, Sevilla Navarro J, Coll Sibina MT, García-Bernal M, Ruiz Llobet A, Badell I, Velasco-Puyó P, Dapena JL, Mañú-Pereira MM. Osmotic gradient ektacytometry: A valuable screening test for hereditary spherocytosis and other red blood cell membrane disorders. Int J Lab Hematol. 2018 Feb;40(1):94-102.


Mañú Pereira M, Ropero P, Loureiro C, Vives Corrons JL. Low affinity haemoglobinopathy (Hb Vigo) due to a new mutation of beta globin gene (c200 A>T; Lys>Ile). A cause of rare anaemia misdiagnosis. Am J Hematol. 2017 Jan 9.


Maria Garcia-Gomez, Andrea Calabria, Maria Garcia-Bravo, Fabrizio Benedicenti, Penelope Kosinski, Sergio López-Manzaneda, Collin Hill, María del Mar Mañú-Pereira, Miguel A. Martín, Israel Orman, Joan-Lluis Vives-Corrons, Charles Kung, Axel Schambach, Shengfang Jin, Juan A. Bueren, Eugenio Montini, Susana Navarro, Jose C. Segovia. “Safe and Efficient Gene Therapy for Pyruvate Kinase Deficiency”. Molecular Therapy 2016 Aug;24(7):1187-98                               

                                              


ACTIVE COLLABORATIONS WITH BIOTECH COMPANIES

Agios Pharmaceuticals, Inc (Cambridge, USA)

Novartis Pharma AG (Basel, Switzerland)

Celgene International II Sàrl (Couvet, Switzerland)

Novartis Farmacéutica S.A. (Barcelona, Spain)

IP: M Mar Mañu Pereira

Projectes

ERN-EuroBloodNet: EUROPEAN REFERENCE NETWORK ON RARE HEMATOLOGICAL DISEASES

IP: M Mar Mañu Pereira
Col·laboradors: -
Entitat finançadora: EUROPEAN COMMISSION
Finançament: 371825
Referència: EUROBLOODNETBR2022_EU4H-ERN2022
Durada: 01/05/2022 - 30/11/2023

ENABLING PERSONALIZED MEDICINE OF SICKLE CELL DISEASE PATIENTS BASED ON INTEGRATIVE DIAGNOSIS OF NEW GENERATION METHODOLOGIES

IP: M Mar Mañu Pereira
Col·laboradors: Pablo Velasco Puyó, Bárbara Tazón Vega, ENABLING PERSONALIZED MEDICINE OF SICKLE CELL DISEASE PATIENTS BASED ON INTEGRATIVE DIAGNOSIS OF NEW GENERATION METHODOLOGIES, Maria Cristina Díaz de Heredia Rubio, ENABLING PERSONALIZED MEDICINE OF SICKLE CELL DISEASE PATIENTS BASED ON INTEGRATIVE DIAGNOSIS OF NEW GENERATION METHODOLOGIES, Thaïs Murciano Carrillo, Victoria Gutierrez Valle, Amira Idrizovic
Entitat finançadora: Instituto de Salud Carlos III
Finançament: 99220
Referència: PI20/01454
Durada: 01/01/2021 - 31/12/2023

ERICA - European Rare dIsease research Coordination and support Action

IP: M Mar Mañu Pereira
Col·laboradors: Claire Diot
Entitat finançadora: EUROPEAN COMMISSION
Finançament: 105250
Referència: ERICA_H2020-SC1-BHC-2020
Durada: 01/03/2021 - 28/02/2025

GENOMED4ALL - Genomics and Personalized Medicine for all though Artificial Intelligence in Haematological Diseases

IP: M Mar Mañu Pereira
Col·laboradors: Anna Collado Gimbert
Entitat finançadora: EUROPEAN COMMISSION
Finançament: 434000
Referència: GENOMED4ALL_H2020-SC1-FA-DTS-2018-20
Durada: 01/01/2021 - 31/12/2024

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