Hepatocyte-Based Therapies for Oxalosis
Airlie House,
Warrenton, VA
June 9, 2002
Meeting Summary
Chairs: Dr. Ira Fox, University of Nebraska and Dr. Dawn Milliner, University of Minnesota
Session I
Drs. Dean Assimos, Laurence Greenbaum, Ross Holmes and Dawn Milliner discussed various aspects of the oxalosis or primary hyperoxaluria (PH) disease. Dr. Assimos gave a brief history of research on the primary hyperoxalurias, including the cloning of the mutant genes underlying the two forms of the disease. He described techniques used to diagnose the disease, discussed early clinical manifestations with emphasis on urolithiasis, and commented regarding the differences between PH1 and the less severe PH2.
Dr. Greenbaum described the symptoms and progression of the disease, including kidney failure and the inadequacy of dialysis to remove oxalate from patients who have developed end-stage renal disease. He noted that hyperoxaluria and its pathogenic consequences are reversible if the disease-causing liver is removed in a liver-kidney transplant. He explained that to prevent disease in a person approximately 25 percent to 40 percent of wild-type enzyme activity is required.
Dr. Holmes reviewed the available animal models of PH, including an AGT knockout mouse, which models PH1, and a GRHPR knockout mouse that is being developed to study PH2. The AGT knockout animal only develops calcium oxalate crystals if there is also reduction of renal mass, such as that which is achieved with unilateral nephrectomy. He mentioned that it is also possible to use various types of cell populations for research.
Finally, Dr. Milliner described the genetic complexity of the disease. Particularly noted were the unique challenges of enzyme replacement therapy for an enzyme whose effective function may be dependent upon an intraperoxisomal location and for a disease caused by an end product of a metabolic pathway (oxalate) that is not amenable to metabolic disposition or to excretion without pathogenic consequences.
Session II
Dr. Ira Fox introduced the session by describing some of the work with liver-kidney transplants for patients with primary hyperoxaluria. Drs. Sanjeev Gupta, Chandan Guha, and Jayanta Roy-Chowdhury then described their recent successes in hepatocyte transplantation in both animal models of Crigler-Najjar Syndrome and a human patient with the disease and in an animal model of Wilson's disease. One significant limitation of conventional hepatocyte transplantation is the limited growth of the engrafted hepatocytes and the persistence of the mutant host cells, which can be a problem in diseases such as hyperoxaluria. The researchers described methods for selective growth advantage, focusing on methods that they are using in animals to ablate the endogenous liver chemically and/or with stereotactic radiation. These techniques appear to allow the transplanted cells to proliferate and eventually replace the majority of the host hepatocytes. Dr. Stephen Strom wrapped up the discussion with a brief description of current research efforts to use transplanted hepatocytes in clinical settings.
Discussion
One of the common mutations in oxalosis patients mistakenly targets 90 percent of the AGT1 protein to the mitochondria instead of the peroxisome. Such patients have marked hyperoxaluria and clinical disease. In the discussion, it was noted that herbivores, like humans, have AGT in peroxisomes only, while carnivores, such as rodents, have the enzyme in mitochondria. The species-specific nature of intracellular AGT distribution led to a general discussion about the adequacy of current animals models of the disease and the need to develop a model that more closely parallels human primary hyperoxaluria. Several other interesting research avenues were suggested during the discussion, including exploring the role of Oxalobacter formigenes in disposition of oxalate from the gastrointestinal tract, elucidating the following:
- Role of bile salts in oxalate transport and the absorption of oxalate from the gut
- Need to identify the liver oxalate transporter
- Practicality of introducing nonhuman oxalate decarboxylase
- Possibilities for stimulating endogenous AGT production or expression
- Need for prognostic indicators
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