Stem Cell-Based and Molecular Therapies

Stem Cell-Based and Molecular Therapies thematic strand aims at promoting interdisciplinary research that can be translated into the development of innovative tools and applications for prevention and treatment of a selected group of disorders. The target disorders – neurodegenerative and ischemic diseases, infection and cancer – rank among the leading causes of death worldwide, and are all exacerbated in an increasingly ageing population with frequently associated comorbidities. For these diseases we lack effective therapies and stem cell-based and molecular therapies are the most promising candidates.
Stem cells are an important source of cells for regenerative medicine applications, in particular for the treatment of ischemic disease. Several clinical trials are underway to investigate their therapeutic effects. Yet, it is of utmost importance to understand the bioactivity of stem cells and eventually to control it, to develop new platforms to improve stem cell survival after transplantation, to generate in vitro systems from stem cells for drug screening and toxicological assessment.

By understanding better how to control the biology of stem cells the Strand is in a unique position to develop new therapies and in vitro systems for drug screening. Similarly, molecular therapies with viral and non-viral vectors have resulted in remarkable successes in therapy and hemophilia, congenital blindness or severe dyslipidemia. The studies of CNC.IBILI researchers show that neurodegenerative disorders, cancer and infectious diseases can also benefit from this approach, by either silencing of pathogenic genes or overexpression of therapeutic gene products. Validation of targets with molecular therapies will also allow translation into effective small molecules-based therapies.

We have the contribution of a multidisciplinary team trained in the best international research centers and integrated in outstanding international networks such as E-rare ERA-net, TBnet, and Marie-Curie networks, as well as the Harvard-Portugal program and MIT-Portugal Program. In addition, all the principal investigators of this thematic strand have strong connections with leading groups abroad either in Europe or USA, such as the Max Planck Institute (Dresden), the Imperial College, University of London, the Broad Institute in Cambridge, or MIT.

The thematic strand is formed by 8 groups contributing to two areas: (i) Molecular Therapy and (ii) Stem Cell Biotechnology. These groups have produced remarkable contributions within the fields of membrane fusion and non-viral gene therapy; were among the first to use of viral vectors to produce models of neurodegenerative disease; generated novel proprietary lipid-based nanoplatforms for drug and siRNA delivery towards cancer cells and tumor microenvironment which originated the spin-off TREAT U, were involved in the drug development program of the first Portuguese medicine that reached the market – Eslicarbazepine (by BIAL); developed innovative platforms to evaluate functional differentiation of neural stem cells, deciphered the 3D structure of promising drug targets in the tuberculosis (TB) pathogen as well as host molecular machinery targeted by TB also as potential drug targets, and generated in vitro models for drug screening and toxicology assessment based on stem cells. Joining these groups with complementary expertise appears therefore obvious and is expected to give the necessary focus to pursue and accomplish the challenging mission of translating into advanced therapies, in this way alleviating diseases and benefiting patients.

Research Groups

Therapy 1: Vectors and Gene Therapy
Therapy 2: Stem cell biotechnology
Therapy 3: Systems and Computational Biology
Therapy 5: Medical Microbiology
Therapy 6: Medicinal Chemistry and Drug Discovery
Therapy 7: Pharmacometrics

Main Goals

This thematic strand aims at treating high morbidity and mortality diseases using two approaches: i) molecular therapy and ii) stem-cell based therapy.

1. Molecular Therapy
The systematic use of molecular therapy approaches is expected to accelerate understanding and treatment of disease. For this we take advantage of viral and non-viral vectors, for nucleic acid and drug delivery aiming at i) establishment of disease models and study of molecular mechanisms and ii) development of new molecular therapeutic approaches. Experimental models of disease (neurodegeneration, cancer and infection, including microbe-gut-brain paradigms) will be established by (a) introduction of specific disease-associated gene sequences in the genome of cell lines, as well as in vivo transduction of rodent tissues using viral vectors platforms; (b) isolation of biological samples including peripheral blood, fibroblasts and tumor cells, including cancer stem cells from patients; (c) reprogramming of patient fibroblasts into induced pluripotent stem cells, to be differentiated into neural cells. These models and patient samples will allow the study of disease-modified pathways and pathogen metabolism – by mRNA- and microRNA-microarray screening complemented by screening of cell death and proliferation, protein aggregation and microbial metabolism and host responses, using whole genome shRNA lentiviral libraries coupled to transcriptional microarray, qPCR and proteomic analysis. Candidate disease pathways will be further investigated by counteracting the dysfunctions upon overexpression and silencing the identified relevant genes in the in vitro and in vivo models. Translational molecular therapy approaches will be investigated for cancer, neurodegenerative (e.g. Machado-Joseph and retinal disease) and infectious diseases using nucleic acids and chemical compounds, and help of protein crystallography and 3D structure scaffolds for drug design.

2. Stem cell-based therapy
The second flagship focuses in stem cell-based therapies for the treatment of ischemic diseases (the major cause of death in Portugal). It includes the development of stem cell-based therapies to treat non-healing wounds in chronic patients (small clinical trial in collaboration with Associação Protectora de Diabéticos de Portugual). Furthermore, this flagship will focus on the development of innovative strategies for cell reprogramming and stem cell modulation/differentiation. Cell reprogramming will focus in the generation and characterization at gene, protein and functional levels of human hematopoietic stem cells, neural stem cells and cardiomyocytes from somatic cells. Work on cell modulation will focus in the development of remotely controlled nanomaterials to perturb endogenous and exogenous stem cells and study its differentiation and engraftment. Finally, this flagship will focus in the development of stem cell-based assays and in silico approaches for drug screening, specifically, the development of cell kits based on vascular cells derived from induced pluripotent stem cells to screen compounds that may have impact in the treatment/prevention of atherosclerosis and blood brain barrier (BBB) permeability.

This thematic strand is expected to generate rapid diagnostics, and innovative therapeutics founding new scientific knowledge, protected and licensed intellectual property and translational benefits through clinical trials for the defined targets.