Recombinant human lactoferrin treatment for global health issues: iron deficiency and acute diarrhea
Iron deficiency and diarrhea are two of the most significant issues for global health. Iron deficiency anemia is the most common nutritional deficiency in the world, affecting nearly 25% of the world population (UNICEF/WHO 1999). The prevalence of iron deficiency in developing countries is illustrated by comparison with other deficiencies: iron deficiency affects 3.5 billion people, while vitamin A and iodine deficiency affect 0.3 billion people and 0.8 billion people, respectively. The prevalence is highest among young children and women of childbearing age (particularly pregnant women). It is estimated that national productivity levels could be raised as much as 20% by correcting iron deficiency in developing countries. Recombinant human lactoferrin (rhLF), expressed and extracted from rice seed, is being evaluated by Ventria Bioscience for use as a dietary supplement to treat iron deficiency and/or iron deficiency anemia. Diarrhea is also a major world health issue. Sixty percent of children who die under age five die of pneumonia, diarrhea or measles. World Health Organization oral rehydration solution (WHO-ORS) is one of the major medical advances in the past 50 years, saving the lives of 1 to 2 million children annually. Many studies have demonstrated similar efficacy of rice-based ORS. There are studies documenting the reduced frequency of diarrhea in breast-fed children and this health improvement is attributed to the antimicrobial action of the human milk proteins lactoferrin and lysozyme. In vitro data document the growth inhibition of the diarrheal associated organisms: rotavirus, ETEC, cholera, salmonella, and shigella by human lactoferrin (hLF) and human lysozyme. Using Ventria's ExpressTecTM system, we have expressed human lactoferrin and human lysozyme in rice. In a rice-based ORS formulation, these proteins have the potential to provide not only the benefits of reduced stool volume and improved weight gain, but also shorten the course of diarrheal episodes via antimicrobial activity against the causative agent.
iron deficiency oral rehydration solution recombinant human lactoferrin
Anzai H, Takaiwa F et al.
2000 Production of human lactoferrin in transgenic plants. Lactoferrin: Structure, Function and Application
. K Shimazaki, H Tsuda, M Tomita, T Kuwata, J Perraudin, Elsevier.Google Scholar
Bi BY, Liu JL et al.
1996 Internalization of human lactoferrin by the Jurkat human lymphoblastic T-cell line. Eur J Cell Biol
(3), 288-296.Google Scholar
Cama RI, Parashar U et al.
1999 Enteropathogens and other factors associated with severe disease in children with acute watery diarrhea in Lima, Peru. J Infectious Diseases
, 1139-1144.Google Scholar
Cash RA, Nalin DR et al.
1970 A clinical trial of oral therapy in a rural cholera treatment center. Am J Trop Med Hyg
, 653-656.PubMedGoogle Scholar
Chong DK, Langridge WH. 2000 Expression of full-length bioactive antimicrobial human lactoferrin in potato plants. Transgenic Res
(1), 71-78.PubMedGoogle Scholar
Cox TM, Mazurier J et al.
1979 Iron binding proteins and influx of iron across the duodenal brush border. Evidence for specific lactotransferrin receptors in the human intestine. Biochim Biophys Acta
(1), 120-128.PubMedGoogle Scholar
Farthing MJG. 2002 Oral rehydration: An evolving solution. J Pediatr Gastroenterol Nutr
(Suppl 1), S64-S67.PubMedGoogle Scholar
Faruque A, Hoque S et al.
1997 Randomized, controlled, clinical trial of rice versus glucose oral rehydration solutions in infants and young children with acute watery diarrhoea. Acta Paediatr
, 1308-1311.PubMedGoogle Scholar
Gera T, Sachdev H. 2002 Effect of iron supplementation on incidence of infectious illness in children: systematic reveiw. BMJ
, 1142-1152.PubMedGoogle Scholar
Gleason GR. 2002 Iron deficiency anemia finally reaches the global stage of public health. Nutr Clin Care
(5), 217-219.PubMedGoogle Scholar
Gomez HF, Ochoa TJ et al.
2003 Human lactoferrin impairs virulence of Shigella flexneri. J Infectious Diseases
, 87-95.Google Scholar
Guerrant RL, Schorling JB, et al.
1992 Diarrhea as a cause and effect of malnutrition: diarrhea prevents catch-up growth and malnutrition increases diarrhea frequency and duration. Am J Trop Med Hyg
, 28-35.PubMedGoogle Scholar
Huang J, Nandi S et al.
2002 Expression of natural antimicrobial human lysozyme in rice grains. Mole Breeding
, 83-94.Google Scholar
Huang JM, Wu LY et al.
2002 Expression of functional recombinant human lysozyme in transgenic rice cell culture. Transgenic Res
(3), 229-239.PubMedGoogle Scholar
Huang N, Wu LY et al.
2001 Tissue specific activity of a glucanase 9 promoter and its use in rice transformation. Plant Sci
(3), 589-595.Google Scholar
Humphrey BD, Huang N et al.
2002 Rice expressing lactoferrin and lysozyme has antibiotic-like properties when fed to chicks. J Nutr
(6), 1214-1218.PubMedGoogle Scholar
Iyer S, Lonnerdal B. 1993 Lactoferrin, lactoferrin receptors and iron metabolism. Eur J Clin Nutr
(4), 232-241.PubMedGoogle Scholar
Kawakami H, Hiratsuka M et al.
1988 Effects of iron-saturated lactoferrin on iron absorption. Agric. Biol. Chem.
(4), 903-908.Google Scholar
Kawakami H, Lonnerdal B. 1991 Isolation and function of a receptor for human lactoferrin in human fetal intestinal brushborder membranes. Am J Physiol
(5 Pt1), G841-G846.PubMedGoogle Scholar
Kosek M, Bern C et al.
2003 The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull World Health Org
(3), 197-204.PubMedGoogle Scholar
Kruzel ML, Harari Y et al.
2000 Lactoferrin protects gut mucosal integrity during endotoxemia induced by lipopolysaccharide in mice. Inflammation
(1), 33-44.PubMedGoogle Scholar
Lonnerdal B. 1985 Biochemistry and physiological function of human milk proteins. Am J Clin Nutr
, 1299-1317.PubMedGoogle Scholar
Lopez de Romana G, Brown K et al.
1989 Longitudinal studies of infectious diseases and physical growth of infants in Huascar, an underprivileged peri-urban community in Lima, Peru. Am J Clin Epidemiol
, 769-784.Google Scholar
Mikogami T, Heyman M et al.
1994 Apical-to-basolateral transepithelial transport of human lactoferrin in the intestinal cell line HT-29cl.19A. Am J Physiol
(2 Pt 1), G308-G315.PubMedGoogle Scholar
Mitra A, Zhang Z. 1994 Expression of a human lactoferrin cDNA in tobacco cells produces antibacterial protein(s). Plant Physiol
(3), 977-981.PubMedGoogle Scholar
Molla A, Ahmed M et al.
1985 Rice-based oral rehydration solution decreases the stool volume in acute diarrhoea. Bull World Health Org
(4), 751-756.PubMedGoogle Scholar
Nandi S, Suzuki YA et al.
2002 Expression of human lactoferrin in transgenic rice grains for the application in infant formula. Plant Sci
, 713-722.Google Scholar
PAHO 1997 Prevention and control of diarrheal diseases, http://126.96.36.199/english/hcp/objectives.Google Scholar
Salmon V, Legrand D et al.
1998 Production of human lactoferrin in transgenic tobacco plants. Protein Expr Purif
(1), 127-135.PubMedGoogle Scholar
Shah S, Yousafzai M et al.
2003 Prevalence and correlates of diarrhea. Indian J Pediatr
(3), 207-211.PubMedGoogle Scholar
Sterling CR, Gilman RH et al.
1991 The role of breast milk in protecting urban Peruvian children agains cryptosporidiosis. J. Protozool
(6), 23S-25S.PubMedGoogle Scholar
Suzuki YA, Lonnerdal B. 2002 Characterization of mammalian receptors for lactoferrin. Biochem Cell Biol
(1), 75-80.PubMedGoogle Scholar
Suzuki YA, Shin K et al.
2001 Molecular cloning and functional expression of a human intestinal lactoferrin receptor. Biochemistry
(51), 15771-15779.PubMedGoogle Scholar
Testa U. 2002 Proteins of iron metabolism
. Boca Raton, Fla., CRC Press.Google Scholar
Togawa J-I, Nagase H et al.
2002 Lactoferrin and experimental colitis: Oral administration of lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance. J Gastroenterology and Hepatology
, 1291-1298.Google Scholar
UNICEF/WHO 1999 Prevention and control of iron deficiency anemia in women and children. Geneva, Switzerland, Report of the UNICEF/WHO Regional Consultation.Google Scholar
van der Strate B, Beljaars L et al.
2001 Antiviral activities of lactoferrin. Antiviral Res
, 225-239.PubMedGoogle Scholar
Victora CG, Bryce J et al.
2000 Reducing deaths from diarrhoea through oral rehydration therapy. Bull World Health Org
(10), 1246-1255.PubMedGoogle Scholar
Victora CG, Smith P et al.
1987 Evidence for protection by breastfeeding against infant deaths from infectious diseases in Brazil. Lancet
, 319-322.PubMedGoogle Scholar
WHO 2003 Micronutrient deficiencies: battling iron deficiency anemia, www.who.int/nut/ida.htm.
WHO/UNICEF 1998 The State of the World's Children 1998, http://www.unicef.org/sowc01.
Yang D, Wu L et al.
2001 Expression of the REB transcriptional activator in rice grains improves the yield of recombinant proteins whose genes are controlled by a Reb-responsive promoter. Proc Natl Acad Sci USA
(20), 11438-11443.PubMedGoogle Scholar
Zaman K, Yunus M et al.
2001 Efficacy of a packagged rice oral rehydration solution among children with cholera and choleralike illness. Acta Paediatr
, 505-510.PubMedGoogle Scholar
Zlotkin S. 2002 Current issues for the prevention and treatment of iron deficiency anemia. Indian Pediatr 39
(2), 125-129.PubMedGoogle Scholar
© Kluwer Academic Publishers 2004