A New and Effective method for intravenous Enyzyme replacement therapy: Late Infantile Batten Disease

Yu Meng, David Sleat, Istvan Sohar, Peter Lobel. CABM, Rutgers University, Piscataway, NJ, 07076, lobel@cabm.rutgers.edu

INTRODUCTION

There is no effective therapy for LINCL. Our laboratory is evaluating treatment regimens in our mouse model to provide proof-of-principle for enzyme replacement therapy for LINCL.

KEY PROJECTS

1. We have developed a

new way of getting TPP1

from the bloodstream into

the brain. This is more

effective than any method

discovered to date for any

enzyme.

1. In principle, a non-

invasive enzyme

replacement therapy for

LINCL is a realistic

possibility.

1. These results provide

strong support for further

study of this remarkable

delivery method.

WHAT THIS MEANS FOR THERAPY

Acknowledgements: This work was supported in part by a Johnson and Johnson Focused Giving Award and NIH R01 NS37918 to PL and a Batten Disease Support and Research Association fellowship to YM

Enzyme replacement therapy has worked well for some lysosomal storage diseases. A synthetic form of the protein that is missing in patients is given to patients, and it travels to the lysosome and clears up storage material.

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4 Cerebral Cortex

LINCL mouse

LINCL mouse treated with TPP1 and Peptide

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LINCL is caused by the loss of a brain enzyme, tripeptidyl peptidase 1. Enzyme replacement therapy for LINCL is difficult because the blood-brain barrier prevents TPP1 administered into the blood entering the brain. To date, there are no good methods to beat the blood-brain barrier.

2

We have developed a new way to help TPP1 move from the bloodstream into the brain. When we inject mice with TPP1 and a special peptide into the tail vein, we can get 8-times higher than normal activity in the brain.

When injected with the peptide, the TPP1 enters the neurons of the brain.

Intravenous treatment of mice with TPP1 alone doesn’t increase lifespan. However, a single timepoint treatment with TPP1 and the peptide extends the lifespan of the LINCL mouse.

Treatment 5

3

Wild-type mouse