Cell Research
The first scientific articles relating to stem cells in Brazil date from the early 1990s, mostly on hematopoietic stem cells and bone marrow transplant. From 2001 on, several groups started reporting work on different sources of stem cells, including murine embryonic stem cells and mesenchymal (adult) stem cells from different sources.
In 2005, stem cell research was recognized by the ministers of science and technology and of health as a strategic area for investment. From 2005 until 2014, approximately US$35 million was invested in regenerative medicine, including US$16 million used for construction of cell culture facilities for the production of clinical-grade stem cells. That led to the creation of the National Network for Cell Therapy, a virtual network of Brazilian scientists conducting research in the field of stem cells, sponsored by the Ministry of Health. In addition, the São Paulo State Funding Agency (FAPESP) funds two centers for stem cell research: the Center for Research in Cell Therapy, which focuses on advanced basic and applied research on stem cells, particularly in the context of autoimmune and hematopoietic diseases; and the Human Genome and Stem-Cell Research Center, which conducts basic and applied research focusing on the human genome, genetic diseases, and stem cells.
Most of the basic and preclinical research performed in Brazil deals with adult stem cells, mostly mesenchymal cells from bone marrow, umbilical cord vein, dental pulp, and adipose tissue. A few groups work with neural and cardiac stem cells. Until 2008, very few groups worked with mouse/human embryonic stem cells. However, with the advent of human induced pluripotent stem cells (hiPSCs) and the establishment of the technology in Brazil, there has been an increase in the number of research projects involving pluripotent stem cells, as discussed below.
In 2008, the first line of human embryonic stem cells (ESC) was derived in Brazil. Since then, two additional human ESC lines have been derived—albeit adequate for research only, not for therapy—and several Brazilian groups started using these pluripotent stem cells in their research. In addition, in an effort to expand embryonic stem cell research in the country, the National Laboratories for Embryonic Stem Cell Research at the University of São Paulo and at the Federal University of Rio de Janeiro distribute these cell lines and offer training in human pluripotent stem cell culture.
In addition to their potential use in regenerative medicine, pluripotent stem cells are an invaluable experimental in vitro system for disease modeling and for the screening of new drugs. Human induced pluripotent stem cells (iPSCs) are particularly interesting for these applications, since one can derive these cells from individuals with specific genetic diseases, creating in vitro models of the disease—what has been called “disease in a dish.” Thus, this is another area of intense research in Brazil, and there have been reports of hiPSCs derived from patients with schizophrenia, autism, and amyotrophic lateral sclerosis (ALS).
In addition to these cell lines, started in 2013, an initiative from the Ministry of Health is generating a bank of human iPSCs from individuals with Down syndrome, cystic fibrosis, polycystic renal disease, anemia, type 1 diabetes, Parkinson’s disease, Rett syndrome, various heart diseases, familial hypercholesterolemia, Gaucher disease, and Alzheimer’s disease. These cells will be used to study the molecular mechanisms of pathogenesis of each disease by comparing the affected cell type from the patients from those of control individuals. Moreover, the affected cells can also be used in the identification and testing of novel drugs for the corresponding disease.
Another important use of human iPSCs is for testing drugs’ efficacy and toxicity. Currently, new drugs are licensed on the basis of efficacy in only 30 percent of the subjects tested. Moreover, these drugs are tested in general populations in Europe and North America and are sold in developing countries without the knowledge of how effective or safe they are for these populations. On the other hand, the need to test drug response in different populations represents an economic and strategic challenge to the pharmaceutical industry, and thus the need to develop in vitro systems where such studies can be performed.
The establishment of a cellular library that represents the genetic diversity of a specific population could be an alternative way of testing drugs for this population before clinical trials. The Brazilian population is one of the most heterogeneous worldwide, a result of its history of colonization and five centuries of interethnic crosses among Europeans (mostly Portuguese), Africans, and Amerindians. One large initiative for the generation of hiPSCs from the Brazilian population to be used for in vitro studies of drug response and toxicity is under way. It takes advantage of the Brazilian Longitudinal Study of Adult Health (ELSA–Brasil, www.elsa.org.br), a multicenter cohort project to investigate incidence and risk factors to chronic pathologies like diabetes and cardiovascular diseases in the Brazilian population. For each participant, a database of exams was established, including clinical and anthropometric examinations. Human iPSCs will be derived from the participants and will be used for in vitro clinical trials of new drugs in the Brazilian population. In addition, since each cell line will be connected to a database of clinical parameters, this library may also enable the identification of cellular phenotypes and molecular mechanisms associated with particular clinical manifestations.
Stem Cell Legislation
In 2005, a legal framework was established to regulate stem cell research and therapy. The Biosafety Law (n. 11.105, March 24, 2005) approves the use of human embryos for research, provided they (1) were produced on or before March 24, 2005; (2) have been frozen for at least three years; or (3) were unviable, with the consent of the parents. After being challenged in the Supreme Court in 2006, the legislation was deemed constitutional in 2008.
Two independent regulatory bodies supervise stem cell research and therapy in Brazil: (1) the National Committee for Research Ethics (CONEP), which analyzes ethical issues related to human stem cell research; and (2) the National Agency for Sanitary Management (ANVISA), which deals with sanitary, safety, and efficacy issues of the use of stem cells in humans. In 2010, ANVISA established a regulation for laboratories working with stem cells for clinical use, the so-called Centers of Cell Technology (CCT). Type I CCTs can collect tissues, minimally manipulate (not including cell culture), and cryopreserve the cells—cord blood banks are an example of type I CCT. In addition to all the activities of a type I, type II CCTs have license to also culture and/or differentiate cells.
Clinical Trials
Brazil has important local advantages for conducting clinical trials. Besides having the legal and regulatory framework for clinical stem cell research, the country has highly qualified human resources, including scientists, technicians, and physicians with experience in conducting clinical trials; excellent hospital facilities with a high concentration of patients in relatively few centers; lower costs of operation for personnel; and adequate infrastructure of services such as clinical research organizations and logistics.
A search in ClinicalTrials.gov in May 2014 yielded 35 results for interventions with stem cells in Brazil—all of them with adult stem cells, mostly from bone marrow. The largest one, initiated in 2005 and sponsored by the Health Ministry, is a multicenter phase III trial using mononuclear fraction of bone marrow for different cardiopathies, including Chaga’s disease–related cardiomyopathy, dilated cardiomyopathy, and acute and chronic heart ischemia. Other clinical studies involve the use of bone marrow or bone marrow derived mesenchymal stem cells for the treatment of spinal cord injury, liver cirrhosis, ischemic retinopathy, epilepsy, pulmonary disease, lupus erythematosus, and critical limb ischemia. Of note, one clinical trial for type 1 diabetes, an autoimmune disease, consisting of autologous bone marrow transplant to reset the patient’s immune system and halt the attack on insulin-producing cells. Although there was some morbidity associated with the procedure, outcomes were promising.
Brazil has established three lines of human ESCs and several groups
