Packages

Work Package 1

Enzyme replacement therapy studies in the mouse model

Work Package Number: 1
Involves Partners 1 and 2

This workpackage aims at a more detailled description of the effect of ERT in the preclinical mouse model. It will also integrate the findings reported in WP2-5 which on the one hand focus on the comparative analysis of alpha mannosidase deficient mice and control mice and on the other hand investigate the effect of ERT in these mice.

It is known from previous experiments performed in the EURAMAN framework (Roces et al. 2004) that the storage correction induced by ERT is time, tissue and dose dependend and of transient nature. Peripheral organs (liver, spleen, kidney, heart) showed a full correction after two repeated injections, while the brain showed a decrease of 74% of the neutral sugars (decrease to 26% of that of the mock injected mice).

Based on these findings, the following studies are to be performed in WP1 and analysed within WP2:

Short term experiments with a relevant number of mice (>20/group) with injections twice a week and analysis (see WP2) every half week until 4 weeks of treatment
Long term treatment of mice with increased enzyme injection frequency (twice a week) until 4-6 months of treatment.
Short and long term treatment of mice with increased enzyme doses (up to 500 mU/g body weight)

Although cat and cattle strains with alpha-mannosidase deficiencies have been described, they are not as appropriate for testing the pathophysiology of the disease and a variety of therapeutic strategies as the murine model. The mouse model has considerable advantages over mannosidosis models in cat and cattle in terms of life span, availability, ease of breeding and control of the genetic background of the affected animals. To our knowledge the described cattle strains are no longer available. However, we are in contact with Dr. Steve Walkley, Sidney Weisner Laboratory of Genetic Neurological Disease New York who still breeds cats with alpha mannosidosis. In case that our mouse experiments are successful we will consider to try ERT-therapy in some selected cats. However, it should be noted that due to the weight differences between cats and mice we will need more than 100 times purified enzyme/for one experiment as compared to an experiment using a 20g mouse.