The discovery could pave the way to future treatments for this inherited blood disease. The research findings appear in the Dec. 19 Advance Online Publication of Nature Medicine.
PROMISING SICKLE CELL DISEASE TREATMENT- UTHealth biochemists reduced the hallmark of sickle cell disease – the sickling of red blood cells – in an animal model of the hereditary blood disease. From left to right are: Yujin Zhang, M.D., Ph.D., Yang Xia, M.D., Ph.D., and Weiru Zhang, M.D.
Sickle cell disease is a disorder that affects red blood cells. The disease, which affects more than 70,000 people in the United States, can result in pain, organ damage and shortened life expectancy, according to the Sickle Cell Disease Association of America, Inc.
By decreasing levels of a signaling molecule called adenosine, the scientists were able to reduce the deformity and destruction of red blood cells and also reduce injury to vital organs in a transgenic mouse model of sickle cell disease.
To gauge the applicability of their animal findings to humans, the research team analyzed adenosine levels in blood samples of people with the disease. They found elevated levels of adenosine. When the researchers decreased adenosine levels, there was reduced sickling of cells.
“Our in vivo studies provide the first compelling evidence that elevated adenosine contributes to chronic sickling in sickle cell disease transgenic mice,” said Yang Xia, M.D., Ph.D., the study’s senior investigator and associate professor of biochemistry and molecular biology at the UTHealth Medical School. “Our research has revealed new therapeutic approaches to treat this life-threatening disease that has puzzled scientists for 100 years.”
Increased adenosine has been linked to other health conditions including Severe Combined Immunodeficiency Disease or SCID (also known as the bubble boy disease). SCID has been associated with a deficiency of the adenosine deaminase enzyme, which degrades adenosine to maintain normal levels.
In the study, researchers used a Food and Drug Administration approved drug for adenosine deaminase deficiency SCID – polyethylene glycol–modified adenosine deaminase (PEG-ADA) – to lower the elevated levels found in the transgenic mouse model with sickle cell disease.
In addition to the PEG-ADA treatment, the researchers identified two other possible ways to reduce the detrimental effects of adenosine signaling in the SCD mouse model. Those include inhibiting one of four adenosine receptors, A2bR or inhibiting a substance known as cAMP-dependent protein kinase A.
Earlier the researchers had linked increased adenosine to priapism, a symptom of sickle cell disease, so they decided to see if increased adenosine contributed to the disease itself, said Yujin Zhang, M.D., Ph.D., the study’s lead author and assistant professor of biochemistry and molecular biology at UTHealth Medical School. “The next step in our research could involve patient trials,” he said.
“The National Heart, Lung, and Blood Institute (NHLBI) supports research into the mechanisms that cause the clinical complications of sickle cell disease,” said Director of the NHLBI’s Division of Blood Diseases and Resources W. Keith Hoots, M.D. “Early data suggest that more than one cellular receptor for adenosine may impact the biology of this genetic disease. Dr. Xia and her colleagues’ work provides support for therapeutic modulation of human adenosine levels as a strategy to reduce morbidity in patients with sickle cell disease.”
Sickle cell disease stems from a defect in hemoglobin, the protein in red blood cells that transports oxygen. Diseased red blood cells can block blood flow and lead to episodes of pain, especially acute chest pain resulting from blockage of pulmonary blood vessels. Some people experience mild symptoms whereas others may have to be hospitalized.
“This research could lead to a paradigm shift in the treatment of sickle cell disease if these results can be translated to effective therapy in humans with sickle cell disease,” said Harinder Juneja, M.D., one of the study’s authors and a professor of hematology at the UTHealth Medical School. “We need new agents that can decrease the sickling of hemoglobin S and the research by Dr. Xia will provide several avenues to address this issue.”
Juneja said newborns in the United States are screened for sickle cell disease. Those with the disease often develop symptoms by their first birthday. The condition can stunt growth and increase susceptibility to infections. Red blood cell destruction due to the stiff sickle red blood cells causes jaundice, anemia and gallstones. Multiple organs can be affected, resulting in acute and chronic complications including acute pain crisis, acute chest syndrome, priapism, stroke, heart failure due to chronic lung disease and renal failure. Patients’ symptoms are managed with pain medications, antibiotics, blood transfusions and surgery. An approved oral drug called hydroxyurea effectively decreases the acute pain crisis and acute chest syndrome in many patients with sickle cell disease, Juneja said. There is no widely available cure.
Other contributors from the UTHealth Medical School include: Dorothy Lewis, Ph.D., professor of internal medicine; Rod Kellems, Ph.D., professor and chair of the Department of Biochemistry and Molecular Biology; Michael Blackburn, Ph.D., professor of biochemistry and molecular biology; Wenzheng Zhang, Ph.D., associate professor of internal medicine; and Louvenia Carter-Dawson, Ph.D., associate professor of ophthalmology and visual science. Former UTHealth postdoctoral students involved in the study include Yingbo Dai, M.D., Ph.D., and Jiaming Wen, M.D. Weiru Zhang, M.D., also contributed to the research. In addition, there were contributors from Metabolon Inc., Durham, N.C., The University of Colorado, Denver, and Central South University, Changsha, Hunan, China.
The study, which is titled “Detrimental effects of adenosine signaling in sickle cell disease,” was supported by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health and China Scholarship Council.
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