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Center develops three research
whose common thread is the transfer of genetic material to the patient's cells
Looking to the future, Hemocentro
invests in the area of gene therapy
PAULO CÉSAR NASCIMENTO
 Unicamp's Hematology and Hemotherapy Center (Hemocentro) is developing three new studies in the field of gene therapy. This revolutionary treatment modality is considered the future of Medicine and consists of the manipulation and transfer of genetic material to the patient's cells with the aim of correcting diseases, replacing the intake of medication or surgery. Included in the select group of main international centers operating in this area, the Hemocentro currently participates in potentially beneficial research for patients with blood diseases, such as hereditary anemia and hemophilia, and arteriosclerosis.
Studies are beneficial for people with hemopathy
One of the works consists of cloning and using the erythropoietin gene (hormone generated in the kidneys and responsible for the production of red blood cells) to increase red blood cell counts. People with kidney failure suffer from anemia because the body produces the hormone insufficiently. To correct the problem, they periodically inject doses of medication containing synthetic erythropoietin into the body.
“The problem, however, is treating patients who have a blockade of this protein, as in the occurrence of some cancers and even AIDS. In other words, the body even produces erythropoietin, but the response to it is not significant. In these cases, excessively high doses of medication are necessary, which makes traditional treatment more expensive and even prohibitive”, says Professor Sara Teresinha Olalla Saad, responsible for the research.
A similar situation, according to her, occurs in cases of thalassemia and sickle cell anemia. Due to the high cost of the drug, it has not been possible to treat patients adequately. According to the specialist, the amount of erythropoietin made available by the State to reference institutions, such as the Hemocentro, is always less than necessary, and even so the monthly cost of a treatment is approximately R$2.000,00 per patient.
“The benefit of gene therapy research is, therefore, to enable other therapeutic options beyond those currently available on the market”, highlights the researcher. “Instead of synthesizing the protein, which is an expensive process, we want to achieve the same results by injecting the gene and letting the body produce it itself, in a more natural way.”
Too many blood cells – The basic characteristic of gene therapy is to cause a change in the DNA of the person with the pathology. In experiments carried out by Hemocentro, the manipulated erythropoietin gene was transferred to anemic mice and dogs through muscle injection. The muscles were able to produce the protein and released the hormone into the bloodstream, increasing the number of red blood cells in the guinea pigs by between 50% and 80%.
The problem is that the treatment was too successful, that is, in some trials an exaggerated increase in red blood cells was found, which triggered thrombosis. Correcting this abnormal performance of the experiment by “turning off” the gene or by inducing the death of only the cell that produces the protein is now one of the concerns of the team led by Sara.
Verify the occurrence of a possible immunological response to the injection, through examination of muscle tissue, and biodistribution of the gene in different tissues other than the one into which it was injected, such as liver, spleen, kidneys, testicles and ovaries, using the amplification technique of DNA, is another measure to be taken.
“Gene therapy involves some operational problems, such as the organism's rejection of introduced genes, even when exactly the same, reported in experiments abroad. So, the current challenge is how to improve efficiency and preserve security measures”, explains Sara.
To make gene therapy with erythropoietin viable in humans, it will be necessary to complete other steps, such as strict control of hormone production and studies in large animals to analyze the concentrations to be used, efficacy and toxicity.
Consolidated position – Since 1990, the Hemocentro has carried out more than 300 research studies in the area of genetics that resulted in publications in journals of international circulation indexed to the SCI. In 1998 he began research in the area of gene therapy, continuing his genetic studies. Around 40 postgraduate students were trained during this period and more than 1000 works were presented at national and international conferences.
“It is true that there is still a long way to go. But Unicamp's Blood Center can be proud of having one of the most solid and efficient structures for research in the area of genetics and gene therapy. Since the first project fully developed on a scientific research platform in the area of molecular biology, in 1990, research in this area has helped Brazil to consolidate its position in the world”, highlights Dr. Sara.
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Hope for hemophiliacs
 Gene therapy also shows promise for the treatment of hemophiliacs, carriers of a hereditary hemorrhagic condition, which affects mainly men, characterized by profuse hemorrhages, caused by minimal subcutaneous, muscular, joint and visceral trauma. It is a disease caused by a deficiency in blood proteins (called factor 8, in the case of hemophilia A, and factor 9, in the case of hemophilia B) responsible for the clotting process.
“It is common for some smaller vessels to rupture in the body, even without trauma, but adequate clotting prevents blood loss. Hemophiliacs, however, can experience intense bleeding, which is very common, within the joints”, explains hematologist Margareth Castro Ozelo.
Responsible for monitoring patients with this condition treated by the Hemocentro, she participates in collaborative international research in which manipulated genes are being introduced into the DNA of human hemophilia B carriers to correct the problem. Brazil, represented by Unicamp, is the only Latin American country to participate in this pioneering study.
“As there is a flaw in this gene, a mutation that leads to a defect in the code of this protein, the idea of gene therapy is to transfer a new and correct sequence of the gene to the target cell so that the patient produces the factor from which needs”, explains Margareth.
She informs that the use of gene therapy in hemophilia B has been around for about 15 years, and approximately six years ago, after the experimental stages in animals, research began in humans in the United States, including four patients selected and monitored by the Blood center.
In the first clinical study, the gene containing the correct code was injected into thigh muscle cells. In a second phase, in a new trial with the same group of hemophiliacs, the target was the liver cell, the organ responsible for producing the protein in people without the disease. The intention was to make the hepatic artery itself produce the necessary protein.
“The results of both works are being evaluated so that the safest and most effective way of continuing the research can be proposed”, explains the specialist.
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Ischemia is simulatedda
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 Another researcher from Hemocentro, Erich Vinicius de Paula, is developing an unprecedented experimental study with rats, in which he tests the effect of gene therapy using two genes in combination, one called Fibroblast Regrowth Factor (FGF) and the other Growth Factor Derived from Platelets (PDGF).
The experiment consists of simulating ischemia in the animal's paw (localized insufficiency of blood supply) similar to what occurs in the lower limbs of humans and treating the problem by introducing two genes cloned in the laboratory into the animal's body. He wants to compare the results of this therapy with those of another gene treatment
developed since the mid-90s, already applied to humans, albeit experimentally, in which scientists use a single gene, the Vascular Endothelial Growth Factor (VEGF).
In both experiments, the aim is for the factors to stimulate the production of new blood vessels and allow for improved irrigation, based on a reaction from the body itself, and without induction using any drug. But the results, according to him, have not yet demonstrated unequivocally that one treatment may be more effective or safer than the other, and whether both may effectively be able to solve the problem.
If the results are positive, the gene therapy proposed by the hematologist could in the future replace the more traditional procedure to treat ischemia, which is revascularization surgery of compromised limbs, in which clogged arteries are replaced. By allowing the production of new vessels, the innovative procedure may also
benefit those patients with an advanced stage of the problem, in whom surgery cannot help, and who are currently undergoing amputations or living with intense painful processes.
Vascular changes such as arteriosclerosis are today the main cause of death in developed countries, according to data from the World Health Organization (WHO). They can appear as a consequence of other diseases, such as diabetes and obesity, and in addition to arterial obstruction in the lower limbs, they can lead to heart attacks and strokes, when they manifest themselves in the heart and brain, respectively.
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