Feasibility of Hepatocyte Transplantation-Based Therapies for Primary Hyperoxalurias

Abstract

Primary hyperoxalurias (PHs) are diseases caused by overproduction of oxalate by hepatocytes. Most patients with PHs develop nephrocalcinosis and renal failure. Combined liver-kidney transplantation is often used as a definitive treatment of PHs, but because of a large body oxalate load at the time of transplantation, the procedure is not always successful. Because all hepatocytes overproduce oxalate, partial liver replacement procedures, such as auxiliary transplantation of a liver lobe or hepatocyte transplantation are not expected to be useful in this disorder. In this paper we describe novel techniques, based on preparative hepatic irradiation and stimulation of hepatocyte mitosis, through loss of liver mass or administration of hepatic growth factor, which permit transplanted wild-type hepatocytes to massively repopulate the liver, replacing up to 90% of the hepatocytes in recipient mouse livers. Application of this procedure in a recently developed Agxt-gene-deleted mouse model of PH1 resulted in marked amelioration of hyperoxaluria. We propose that further refinement of the different components of this procedure may permit early cell-based therapies of PHs, thereby preventing renal failure and its complications.

Construction of liver tissue in vivo with preparative partial hepatic irradiation and growth stimulus: investigations of less invasive techniques and progenitor cells

“…We measured the levels of serum HGF, which is known as a strong stimulator for hepatocytes growth. Although supplying HGF via an adenovirus vector was demonstrated to induce proliferation of transplanted hepatocytes (10,11,14), PVBL did not increase the levels of HGF, as observed in the clinical PVE study (16). Liver regeneration is regulated by an orchestrated and complex response, involving not only HGF, but also various kinds of mediators.…”

“…Although these results are very attractive, hepatectomy is too invasive to be carried out in patients. Instead of hepatectomy, Fas-mediated apoptosis of host hepatocytes (9) or administration of a recombinant adenovirus vector expressing hepatocyte growth factor (HGF) (10,11) has been successful in inducing massive repopulation of transplanted hepatocytes. However, these strategies appear difficult to implement clinically because of potential toxicity.…”

Hyperoxaluria Is Reduced and Nephrocalcinosis Prevented with an Oxalate-Degrading Enzyme in Mice with Hyperoxaluria

“…We tested this agent in two experimental models with hyperoxaluria: alanine-glyoxylate aminotransferase knockout mice (AGT1KO) [8,9,10], and in AGT1KO mice challenged with ethylene glycol (EG) [10], since mice develop nephrocalcinosis and kidney failure [10] that are characteristic of disease progression in human PH1.Therefore, in the present study we hypothesized that administration of OxDc-CLEC, as an oral agent, will reduce hyperoxaluria and ameliorate nephrocalcinosis and urolithiasis in experimental mice.…”

Hepatocyte transplantation and drug-induced perturbations in liver cell compartments

“…5,6 In this way, transplanted cells could repopulate the liver, where in specific situations the kinetics of liver repopulation reflected loss of native hepatocytes. [7][8][9] In healthy animals, genotoxic manipulations were particularly effective in promoting such liver repopulation with healthy cells. However, further insights are necessary to obtain pharmacologic approaches for repopulating the liver, particularly for clinical applications.…”