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A New Step in the Treatment of Sickle Cell Disease Published as part of the Biochemistry series “Biochemistry to Bedside” Paul R. Ortiz de Montellano* University of California, San Francisco, San Francisco, California 94158-2517, United States
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The sickle cell trait has a protective effect against malaria, which explains its prevalence in certain geographic areas.2 In the United States alone, the annual cost of treating sickle cell disease was estimated in 2009 as $1.1 billion.3 Bone marrow transplants, for which there is limited availability, provide the only current cure for sickle cell disease. In the absence of a more general, safe, and accessible genetic cure, therapies for sickle cell disease focus on the symptoms and not the cause. These treatments include pain medication, infection prevention with antibiotics, hydration, and the use of hydroxyurea, which increases the level of expression of fetal hemoglobin. The development of L-glutamine as a treatment for sickle cell disease is largely due to the efforts of Yutaka Niihara and colleagues at the UCLA School of Medicine. A number of studies have shown that erythrocytes from sickle cell patients are more sensitive to oxidative damage than those from normal individuals. This allowed Dr. Niihara’s team to search for antioxidants that might be of therapeutic value, a search that led them to investigate the relatively high content of nicotine adenine dinucleotide (NAD+) in sickle cells. They reported in 1997 that sickle cells have a higher level of active transport and utilization of glutamine, an amino that is required for NAD+ synthesis.3 They then demonstrated that L-glutamine administration modestly increases NAD+ levels in sickle cells but
milestone was reached in July of this year when Endari, the first new therapeutic for sickle cell disease in 50 years, was approved by the Food and Drug Administration (FDA). Endari is the commercial name assigned to the amino acid L-glutamine when it is administered to alleviate the symptoms of sickle cell disease or β-thalassemia. Sickle cell disease refers to a group of genetic disorders in which hemoglobin molecules are expressed with mutations that cause the normally spherical erythrocytes to form sickled, angular cells that clump and flow poorly in the blood vessels. In the most common form of the disease, the normal hemoglobin A is replaced by hemoglobin S, in which the β-chain has a valine rather than a glutamic acid at position 6 (E6V).1 In the deoxy form of this mutant, the mutated site is exposed, causing the formation of aggregated molecules and fibrous precipitates. Individuals who inherit a copy of the mutant gene from both parents have full blown sickle cell disease. The pathology of this disease includes anemia, severe pain, life-threatening infections, organ damage, and early death. People with one rather than two copies of the sickle cell gene are considered to have the sickle cell trait. They are carriers of the disease but do not suffer its severe symptoms. Approximately 4 million people in West and Central Africa, 500,000 to 1 million people in South America, and 100,000 people in the United States have sickle cell disease.
Scheme 1. Glutaminase Activity of NAD Synthetase Provides Ammonia That Is Utilized by the Synthetase Activity To Convert the AMP Derivative of Nicotinic Acid Adenine Dinucleotide to the Nicotinamide Product NAD
Received: August 14, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.biochem.7b00785 Biochemistry XXXX, XXX, XXX−XXX
Biochemistry
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more significantly increases the redox potential defined by the ratio of NADH to the sum of NADH plus NAD+.4 This change in NAD redox potential appears to decrease their sensitivity to oxidative stress. L-Glutamine may have additional beneficial effects by facilitating protein and glutathione synthesis. L-Glutamine facilitates NAD+ synthesis as the substrate for the glutaminase activity of NAD synthetase, which uses the ammonia it releases from glutamine to convert nicotinic acid adenine dinucleotide to nicotinamide adenine dinucleotide (Scheme 1).5 These and early clinical studies of L-glutamine as a treatment for sickle cell disease resulted in a patent in 1997 that underlies the introduction of Endari by Emmaus Life Sciences. It is not a cure, but a Phase III clinical trial indicated that it significantly reduced the frequency of sickle cell crisis in patients receiving the drug. The Oncology Drugs Advisory Committee of the FDA, influenced by the absence of approved therapies for the condition, recommended approval despite complications in the statistical analysis of the data. We are hopeful this first step will be followed by further strides in the treatment of this painful and devastating disease.
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AUTHOR INFORMATION
Corresponding Author
*Telephone: 415 476-2903. E-mail:
[email protected]. Notes
The author declares no competing financial interest.
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REFERENCES
(1) Hunt, J. A., and Ingram, V. M. (1958) Allelomorphism and the chemical differences of the human haemoglobins A, S and C. Nature 181, 1062−1063. (2) Serjeant, G. R. (2010) One hundred years of sickle cell disease. Br. J. Haematol. 151, 425−429. (3) Niihara, Y., Zerez, C. R., Akiyama, D. S., and Tanaka, K. R. (1997) Increased red cell glutamine availability in sickle cell anemia: Demonstration of increased active transport, affinity, and increased glutamate level in intact red cells. J. Lab. Clin. Med. 130, 83−90. (4) Niihara, Y., Zerez, C. R., Akiyama, D. S., and Tanaka, K. R. (1998) Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential. Am. J. Hematol. 58, 117−121. (5) De Ingeniis, J., Kazanov, M. D., Shatalin, K., Gelfand, M. S., Osterman, A. L., and Sorci, L. (2012) Glutamine versus ammonia utilization in the NAD synthetase family. PLoS One 7 (6), e39115.
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DOI: 10.1021/acs.biochem.7b00785 Biochemistry XXXX, XXX, XXX−XXX
