Therapeutic application of immunoliposomes in experimental mesangial proliferative glomerulonephritis

Background
IgA nephropathy, the most frequent glomerulonephritis worldwide, occurs histologically mostly as mesangial proliferative glomerulonephritis and frequently leads to progressive renal failure despite treatment attempts. Furthermore, systemic delivery of immunosuppressive agents causes unwanted side-effects. Thus, new strategies, like specific drug delivery to glomerular mesangial cells, are of great clinical interest. We have recently demonstrated, that rat mesangial cells can be selectively targeted by the use of OX7-immunoliposomes (OX7-IL) directed against the Thy1.1 antigen. These immunoliposomes delivered doxorubicin to mesangial cells and caused a visible pharmacologic effect in the glomerular mesangium without any noticeable toxicity in other organs.

Hypothesis
(1) OX7-IL can be loaded with therapeutic molecules, such as specific siRNA and conventional drugs, that are known to have potent anti-inflammatory effects in glomerular mesangial cells.
(2) Therapeutic agents can be delivered in OX7-IL with high specificity to glomerular mesangial cells in diseased rats.
(3) Acute anti-Thy1.1 nephritis can be treated more specifically and effectively by the application of therapeutic agents delivered in OX7-IL, than with their conventional systemic administration in free form.

Specific Aim
The principle aim of the study consists in the therapy of experimental mesangial proliferative glomerulonephritis (anti-Thy1.1 nephritis) by directed drug delivery to the mesangial cells that are responsible for this disease. Novel experimental agents and conventional drugs with known anti-inflammatory effects in mesangial cells will be encapsulated in our previously developed OX7-IL. These constructs will be evaluated for their capacity to revert the inflammatory mesangial cell phenotype to the normally occurring quiescent state.

Experimental Design
Studies are performed in three parts, containing in vitro and in vivo investigations:
Part 1 consists of the loading of OX7-IL with therapeutic agents, such as MMP-2 siRNA, YB-1 siRNA, synthetic matrix metalloproteinase (MMP) inhibitors, prednisolone, and mycophenolic acid (MPA). Preliminary results already show the feasibility of the loading of various agents into our OX7-IL.
In Part 2, cultured mesangial cells are exposed to OX7-IL with encapsulated therapeutic agents. Based on results of these studies, the respective OX7-IL will be selected for subsequent therapeutic applications.
In Part 3, the chosen OX7-IL are injected into rats suffering from anti-Thy1.1 nephritis. Analyses of the therapeutic effect in these animals are performed on the histological and on the functional level.

Investigators
Prof. Hans-Peter Marti

Sponsor
Swiss National Science Foundation, Project no. 114054