Late Infantile Batten Disease

Martin L. Katz, Principal Investigator, University of Missouri School of Medicine, Mason Eye Institute, Columbia, MO 65212 E-mail: katzm@health.missouri.edu

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APPROACHES FOR TREATING CLN2

CLN2 Therapy Studies from the Neurodegenerative Diseases Research Laboratory

The cause of CLN2 is the lack of a protein

(enzyme) called tripeptidyl peptidase-1 (TPP1).

TPP1 is required for the breakdown of old damaged

proteins that cells need to get rid of.

If TPP1 is missing or defective the proteins and

fragments cannot be chopped up properly so they

aggregate and build up inside cells

2 The aggregates that accumulate in nerve cells in

CLN2 give off a golden yellow glow when slices of

tissue are viewed with fluorescence microscopy.

Brain Brain Spinal Cord

5 It should be possible to cure CLN2 by

providing nerve and other cells with the

normal form of the TTP1 Protein.

Cells will take up TPP1 supplied to them.

The TPP1 protein will attach

to the surfaces of most cells.

After it attaches, the protein

is taken up into cells in small

vesicles. These vesicles

deliver the protein to a

specialized structure in the

cell called the lysosome. In

the lysosome the TPP1

enzyme carries out its

normal function of breaking

down old and damaged

proteins.

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4 TPP1 can be delivered widely throughout

the brain and spinal cord via the cerebral

spinal fluid.

Three Approaches for Delivering TPP1 to

the Cerebrospinal Fluid

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Enzyme Infusion

Gene Therapy

Stem Cell Delivery

These approaches for therapy are being

tested in a Dachshund model for CLN2.

TPP1 is made by cells in culture, purified, and

then infused into the CSF. A clinical trial using

this approach is planned by BioMarin for 2013.

Copies of the TPP1 gene are made by cells in

culture, purified, and then infused into the

CSF. The genes are taken up by cells in the

brain and direct the cells to make and release

the TPP1 protein which then flows through the

CSF.

Cultured stem cells are programmed to make

large amounts of the TPP1 protein. These cells

are implanted into the CSF where they take up

residence and release the protein.

INTRODUCTION

A primary goal of the Neurodegenerative Diseases Research Laboratory (NDRL) is to develop a cure for the CLN2 form of Batten disease.

Using a dog model we are evaluating 3 approaches to treatment: enzyme replacement therapy; gene therapy; and stem cell therapy.

The cerebrospinal fluid

(CSF) is made in the brain

and circulates around the

entire brain and the spinal

cord.

The CSF flows through the

subarachnoid spaces where it

is in very close contact with

most structures and cells of the

brain.