[fahre001]

Hi Everyone!
My first time here. Just wanted to drop a line and let you know about our campaign to cure diabetes using islet xenotransplantation.

Type 1 diabetes is an autoimmune disease that results in the permanent destruction of insulin producing beta cells of the pancreas. Current management involves daily blood sugar testing, insulin injections, and careful meal planning. But insulin only controls Diabetes-it doesn’t cure it. Type 1 Diabetes Mellitus continues to be a therapeutic challenge and burden to patients, their families, and society (more than 1 million U.S. citizens are affected). Hypoglycemia (low blood sugar) and hyperglycemia (high blood sugar levels) result in acute and chronic complications, disability, pain, fears, worries, and discrimination. More than 50% of patients experience some chronic complication, which can lead to such devastating conditions as kidney failure and diabetic retinopathy.

Although pancreas transplantation has shown great promise for treating Diabetes, a limited donor supply (from cadavers) will never meet the demand. Fortunately, investigators at the Diabetes Institute for Immunology and Transplantation at the University of Minnesota have been able to achieve long-term diabetes reversal (>180 days) in diabetic monkeys after porcine islet xenotransplantation. Similar results have been observed by researchers at the Emory University School of Medicine.

This wouldn’t be the first time that pigs have come to the rescue for Diabetes. Until a human insulin drug was made (in 1978 by Genentech), Diabetes patients routinely injected pig insulin. The promise for this therapy is so great that clinical trials of pig-to-human islet xenotransplantation began last year in Russia, and they will soon start in the United States. Procedures for improving the tolerance of patients to pig cells are currently under development around the world. We believe that the prevention of zoonotic transmission of pathogens from donor pigs to patients is crucial for clinical application of porcine xenotransplantation. Although husbandry in a biosecure environment can eliminate most risk, endogenous agents such as porcine endogenous retroviruses (PERV) require special attention. Indeed, upon co-cultivation of pig and human cells, PERV inefficiently traverses the species barrier. Although no evidence of pig to human transfer has ever been observed in vivo, it is prudent to develop pigs with a reduced genetic potential for PERV transmission.

Jónsson et al showed that porcine endogenous retrovirus (PERV) transmission from pig to human cells in long-term co-culture experiments is reduced to nearly undetectable levels by expressing human APOBEC3G in pig cells. This constitutes a compelling proof-of-principle demonstration that APOBEC3 proteins can be used to fortify the innate anti-viral defenses of cells to prevent the zoonotic transmission of an endogenous retrovirus. Engineered pigs that specifically rescue or eliminate potential zoonosis will answer public concerns about safety and PERVless pigs will become the standard resource for xenotransplantation.

We propose to develop pigs that are transgenic for the human APOBEC3G gene using technology developed by the Fahrenkrug lab at the University of Minnesota. Engineered pigs developed from this project will be provided to University of Minnesota clinicians as they move islet xenotransplantation to clinical trials.