Italian scientists pioneering a new gene transfer treatment for the blood disorder β-thalassemia have successfully completed preclinical trials, claiming they can correct the lack of beta-globin (β-globin) in patients' blood cells which causes the disease. The research, published in EMBO Molecular Medicine, reveals how gene therapy may represent a safe alternative to current cures that are limited to a minority of patients.
The disorder β-thalassemia, also known as Cooley's anemia, is caused when a patient cannot produce enough of the β-globin component of haemoglobin, the protein used by red blood cells to carry oxygen around the body. The lack of β-globin causes life threatening anemia, leading to severe damage of the body's major organs. The condition is most commonly found in Mediterranean, Middle Eastern and Asian populations.
"Currently treatments are limited to lifelong regular blood transfusions, and iron chelation to prevent fatal iron overload. The alternative is bone marrow transplantation, an option open to less than 25% of patients," said Dr Giuliana Ferrari from the San Raffaele Telethon Institute for Gene Therapy in Milan. "Our research has focused on gene therapy: by transplanting genetically corrected stem cells we can restore haemoglobin production and overcome the disorder."
Diseases of the blood are good targets for gene therapy because it is possible to harvest stem cells from the patient's bone marrow. The team developed a tool to deliver the correct gene for ß-globin into these harvested cells, a viral vector they called GLOBE.
The cells can then be genetically modified with GLOBE to restore hemoglobin production before being re-administered back into the patient via intravenous injections. The important focus of this work was not only to show that GLOBE can restore haemoglobin production in human cells, but that this genetic transfer-based approach does not impair the biological features of the cells and is not associated with any intrinsic risk for the human genome.
This research is not only crucial for developing a cure for one disease, but as Dr David Williams from the Harvard Medical School says, it may advance the entire discipline of gene therapy research
"This work represents the kind of translational studies that are required to move human investigations forward but are often difficult to fund and publish," said Williams. "Considering the inherent difficulties accompanying human research, studies like those reported in EMBO Molecular Medicine are extremely important for moving the field forward." As the Milan based team can now correct the defective production of beta-globin in patients' blood cells the next step will be to place the corrected cells back into the patient, a step which has already proven successful in mice.
Successful gene therapies are the results of very long studies and our research represents the most comprehensive pre-clinical analysis ever performed on cells derived from thalassemic patients" concluded Ferrari. "We believe this study paves the way forward for the clinical use of stem cells genetically corrected using the GLOBE vector."
Source:
Ben Norman
Wiley-Blackwell
7/26/10
Researchers discover genetic explanation for non-diabetic kidney disease in African-Americans
Variants in the APOL1 gene help explain high rates of renal disease in individuals of recent African ancestry; authors speculate that these variants originally evolved as a survival mechanism against parasitic disease in Africa
Kidney disease is a growing public health problem, with approximately half a million individuals in the United States requiring dialysis treatments to replace the function of their failed kidneys. The problem is particularly acute among African-Americans, whose rates of kidney disease are four times higher than those of European Americans.
As reported online this month by the journal Science, collaborating research groups found that patients with focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) harbored variants in the APOL1 gene that changed the ApoL1 protein sequence. These variants are commonly found in individuals of recent African ancestry.
Furthermore, in a twist of evolutionary medicine, the disease-causing variants may have protected Africans against a lethal parasite, explaining why these genetic variants are so common in the population today.
Researchers at Wake Forest University Baptist Medical Center contributed to and participated in this scientific team, led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and the Universite Libre de Bruxelles. Together, they discovered a genetic explanation - with evolutionary roots - for the higher incidence of non-diabetic kidney disease in African-Americans.
"We found that the APOL1 risk genes for renal disease occur in more than 30 percent of African-American chromosomes," explained co-senior author Martin Pollak, M.D., chief of nephrology at BIDMC and associate professor of medicine at Harvard Medical School. "In fact, the increased risk of kidney disease in individuals who inherited two copies of these variant forms of APOL1 is reported to be approximately 10-fold."
FSGS is a form of injury to the kidney's filtering system, which causes proteins to be lost into the urine and gradually reduces kidney function. ESKD, or end-stage kidney disease, is defined by kidney failure that has progressed to the point that the patient requires dialysis or kidney transplantation.
It has long been thought that high blood pressure is a common cause of end stage kidney disease in African-Americans," said study co-researcher Barry Freedman, M.D., John H. Felts III Professor and chief of the section on nephrology at WFUBMC. "However, the strong association between variants in the APOL1 gene and hypertension-attributed kidney disease suggested that this kidney disease truly resides in the spectrum of FSGS and is not due to hypertension as was initially believed."
More than 2,000 study participants from the southeastern United States were recruited to the study by WFUBMC.
Last year, Freedman led a team of WFUBMC researchers who found that genetic variation near the MYH9 gene on chromosome 22 was also associated with increased risk of hypertension-attributed kidney disease in African-Americans. However, because genome analyses had shown a strong signal of natural selection in the region containing both the MYH9 and APOL1 genes, the authors reasoned that the location of the disease-causing genetic variants was in a broader region. They also predicted that the frequency of these variants would be markedly different between European-Americans and Africans.
Using data from the 1000 Genomes Project DNA data bank, the authors identified candidate genetic variants and tested for their presence in DNA sample sets. They found that two APOL1 variants - dubbed G1 and G2 - were associated with an increased risk of both FSGS and hypertension-attributed ESKD in African-Americans.
"G1 and G2 both changed the coding sequence of APOL1," Pollak explained. "Further analyses revealed that these very same genetic variants [G1 and G2] conferred human immunity against the parasite responsible for sleeping sickness."
African sleeping sickness is caused by an African trypanosome parasite, which is transmitted by the tsetse fly. The disease, which produces severe nervous system disorders that can ultimately lead to brain damage, coma and death, is estimated to affect tens of thousands of people, but is not found outside of Africa.
The APOL1 protein circulates in the blood and helps defend against trypanosomes, a finding initially discovered by co-senior author Etienne Pays, Ph.D., of the Universite Libre de Bruxelles, in Belgium. In the current study, Pays' laboratory found that the plasma from patients harboring the G1 and G2 variants inactivated the trypanosomes that cause the deadliest forms of African Sleeping Sickness, as did the APOL1 protein with these same variants inserted.
"We were excited that our findings appeared to relate kidney disease in the United States with human evolution and parasite infection in Africa," Pollak said. "While there are many details that remain to be clarified in future studies, we do know that sickle-cell disease is a well-established precedent for this model, in which one copy of the mutation confers protection against a parasitic infection but two copies of the mutation can cause severe disease." Pollak explained that, when present in a single copy, certain hemoglobin mutations protect against malaria. But two copies cause sickle cell disease or thalassemia, severe red-blood cell diseases.
"It appears that we may have found a similar situation in APOL1," Pollack added. "Consequently, while these genetic variants protect against sleeping sickness, they also greatly increase a person's susceptibility to kidney disease. We hope that these new findings will not only lead us to a better understanding of the underlying mechanisms leading to kidney failure, but will also help us develop new ways to treat trypanosome infection and kidney disease."
Kidney disease is a growing public health problem, with approximately half a million individuals in the United States requiring dialysis treatments to replace the function of their failed kidneys. The problem is particularly acute among African-Americans, whose rates of kidney disease are four times higher than those of European Americans.
As reported online this month by the journal Science, collaborating research groups found that patients with focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) harbored variants in the APOL1 gene that changed the ApoL1 protein sequence. These variants are commonly found in individuals of recent African ancestry.
Furthermore, in a twist of evolutionary medicine, the disease-causing variants may have protected Africans against a lethal parasite, explaining why these genetic variants are so common in the population today.
Researchers at Wake Forest University Baptist Medical Center contributed to and participated in this scientific team, led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and the Universite Libre de Bruxelles. Together, they discovered a genetic explanation - with evolutionary roots - for the higher incidence of non-diabetic kidney disease in African-Americans.
"We found that the APOL1 risk genes for renal disease occur in more than 30 percent of African-American chromosomes," explained co-senior author Martin Pollak, M.D., chief of nephrology at BIDMC and associate professor of medicine at Harvard Medical School. "In fact, the increased risk of kidney disease in individuals who inherited two copies of these variant forms of APOL1 is reported to be approximately 10-fold."
FSGS is a form of injury to the kidney's filtering system, which causes proteins to be lost into the urine and gradually reduces kidney function. ESKD, or end-stage kidney disease, is defined by kidney failure that has progressed to the point that the patient requires dialysis or kidney transplantation.
It has long been thought that high blood pressure is a common cause of end stage kidney disease in African-Americans," said study co-researcher Barry Freedman, M.D., John H. Felts III Professor and chief of the section on nephrology at WFUBMC. "However, the strong association between variants in the APOL1 gene and hypertension-attributed kidney disease suggested that this kidney disease truly resides in the spectrum of FSGS and is not due to hypertension as was initially believed."
More than 2,000 study participants from the southeastern United States were recruited to the study by WFUBMC.
Last year, Freedman led a team of WFUBMC researchers who found that genetic variation near the MYH9 gene on chromosome 22 was also associated with increased risk of hypertension-attributed kidney disease in African-Americans. However, because genome analyses had shown a strong signal of natural selection in the region containing both the MYH9 and APOL1 genes, the authors reasoned that the location of the disease-causing genetic variants was in a broader region. They also predicted that the frequency of these variants would be markedly different between European-Americans and Africans.
Using data from the 1000 Genomes Project DNA data bank, the authors identified candidate genetic variants and tested for their presence in DNA sample sets. They found that two APOL1 variants - dubbed G1 and G2 - were associated with an increased risk of both FSGS and hypertension-attributed ESKD in African-Americans.
"G1 and G2 both changed the coding sequence of APOL1," Pollak explained. "Further analyses revealed that these very same genetic variants [G1 and G2] conferred human immunity against the parasite responsible for sleeping sickness."
African sleeping sickness is caused by an African trypanosome parasite, which is transmitted by the tsetse fly. The disease, which produces severe nervous system disorders that can ultimately lead to brain damage, coma and death, is estimated to affect tens of thousands of people, but is not found outside of Africa.
The APOL1 protein circulates in the blood and helps defend against trypanosomes, a finding initially discovered by co-senior author Etienne Pays, Ph.D., of the Universite Libre de Bruxelles, in Belgium. In the current study, Pays' laboratory found that the plasma from patients harboring the G1 and G2 variants inactivated the trypanosomes that cause the deadliest forms of African Sleeping Sickness, as did the APOL1 protein with these same variants inserted.
"We were excited that our findings appeared to relate kidney disease in the United States with human evolution and parasite infection in Africa," Pollak said. "While there are many details that remain to be clarified in future studies, we do know that sickle-cell disease is a well-established precedent for this model, in which one copy of the mutation confers protection against a parasitic infection but two copies of the mutation can cause severe disease." Pollak explained that, when present in a single copy, certain hemoglobin mutations protect against malaria. But two copies cause sickle cell disease or thalassemia, severe red-blood cell diseases.
"It appears that we may have found a similar situation in APOL1," Pollack added. "Consequently, while these genetic variants protect against sleeping sickness, they also greatly increase a person's susceptibility to kidney disease. We hope that these new findings will not only lead us to a better understanding of the underlying mechanisms leading to kidney failure, but will also help us develop new ways to treat trypanosome infection and kidney disease."
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