Research update on intravenous Enyzyme replacement therapy for Research update on intravenous Enyzyme replacement therapy for Late Infantile Batten Disease Late Infantile Batten Disease Yu Meng, David Sleat, Peter Lobel. Yu Meng, David Sleat, Peter Lobel. CABM, Rutgers-RWJMS, Piscataway, NJ, 08854, [email protected] CABM, Rutgers-RWJMS, Piscataway, NJ, 08854, [email protected] 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 explored 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. 2. Chronic intravenous enzyme replacement therapy is effective in our mouse model. 3. In principle, a non-invasive enzyme replacement therapy for LINCL is a realistic possibility. 4. These results provide strong support for further study of this remarkable delivery method. WHAT THIS MEANS FOR THERAPY 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 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. 1 4 Cerebral Cortex LINCL mouse LINCL mouse treated with TPP1 and Peptide 6 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 neurons throughout the brain. 3 Wild-type mouse Treatment of LINCL mice started at 6 weeks of age. For acute treatment, mice were administered five daily doses of TPP1 + peptide. This experiment is ongoing. 5

2014 BDSRA Meng Sleat Lobel LINCL

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Page 1: 2014 BDSRA Meng Sleat Lobel LINCL

Research update on intravenous Enyzyme replacement therapy for Research update on intravenous Enyzyme replacement therapy for Late Infantile Batten DiseaseLate Infantile Batten Disease

Yu Meng, David Sleat, Peter Lobel. Yu Meng, David Sleat, Peter Lobel. CABM, Rutgers-RWJMS, Piscataway, NJ, 08854, [email protected], Rutgers-RWJMS, Piscataway, NJ, 08854, [email protected]

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 explored 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.

2. Chronic intravenous enzyme replacement therapy is effective in our mouse model.

3. In principle, a non-invasive enzyme replacement therapy for LINCL is a realistic possibility.

4. These results provide strong support for further study of this remarkable delivery method.

WHAT THIS MEANS FOR

THERAPY

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.

4Cerebral Cortex

LINCL mouse

LINCL mousetreated with TPP1 and Peptide

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.

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 neurons throughout the brain.

Wild-type mouse

Treatment of LINCL mice started at 6 weeks of age. For acute treatment, mice were administered five daily doses of TPP1 + peptide. This experiment is ongoing.