Astroviruses are small, non-enveloped icosahedral viruses with a single-stranded, messenger-sense RNA genome and are known to infect both mammals and birds. They are estimated to cause 2-17% of children's diarrheal illness worldwide. Astroviral infection can be especially devastating for children with malnutrition, intestinal parasites, or both. Even in developed western countries human astrovirus (HAstV) causes a significant economic loss due to parents taking time off from work to care for sick children. This trend of economic loss is likely to worsen as increasing numbers of mothers enter the workforce. Prevention or treatment of astrovirus infection in children would have a significant economic impact on physician and emergency department visits and lost workdays. In poultry farming, turkey astrovirus has a major economic impact on the turkey farming industry. In particular, turkey astroviruses cause a rapidly fatal viremic sepsis in young turkeys suggestive of overwhelming immunologic cascade that likely involves, and may be driven by, the complement system. Veterinary therapeutics designed to prevent or mitigate the damage of turkey astrovirus would be a significant development for this industry.
There is a great need for complement inhibitors. Currently, no anti-complement therapies are approved for use in humans, despite the known morbidity and mortality associated with complement disregulation in many disease processes, including such autoimmune diseases as systemic lupus erythematosus, myasthenia gravis, and multiple sclerosis. The impact of complement-mediated tissue injury in such a diverse array of diseases has driven the development of many complement inhibitors with an estimated market of between $2-4 billion annually. For a review on complement therapeutics as of 2003, please see the review article by B. P. Morgan and C. L. Harris entitled, “Complement therapeutics; history and current progress” (B. P Morgan and C. L. Harris, 2003. Molec. Immunol. 40, 159-170). The astrovirus coat protein appears to have extremely strong effects on the complement system, suggesting that the ‘active’ portion of the protein may have clinical utility in decreasing tissue damage from complement-mediated diseases. There are currently no commercially available anti-complement specific immunomodulators. There is some evidence that IVIg (intravenous immuneglobulin) in high doses has anti-complement effects that may explain its utility in some autoimmune diseases. IVIg is extremely expensive and has safety concerns because it is derived from the blood of hundreds of donors.
Current candidate compounds for anti-complement therapeutics have the significant disadvantage of acting too broadly, or in some cases are not viable due to toxicity. For example, the most powerful anti-complement substance known to date, cobra venom factor (CVF), is capable of virtually depleting all C3 in the plasma by acting as a stable C3 convertase (C3bBb). However, CVF is essentially untenable as a therapy due to the uncontrolled complement activation that results in a prolonged period of decomplementation and vulnerability to overwhelming infection in some experimental models (Younger, J. G. et al., 2001. J. Appl. Physiol. 90, 2289-2295). Antibody response to the CVF would likely also make the therapeutic benefit of this compound too short-lived to be ultimately useful in the treatment of chronic disease. The ideal anti-complement therapeutic method would be as effective in complement depletion as CVF but less toxic and less antigenic when administered to the host. Astrovirus coat proteins and derivatives thereof are capable of regulating complement cascade proteins to an extent comparable with CVF, and thereby are useful for treatment or prevention of complement-mediated tissue damage and mitigation of complement related diseases.
USPTO Backgrounds
USPTO Backgrounds