| ZyStor has developed a proprietary peptide-based targeting technology that allows more efficient delivery of therapeutic enzymes to the lysosome and is thus applicable to the treatment of lysosomal storage diseases in general. This proprietary technology is termed GILT because the peptide tag replaces the M6P carbohydrate as the moiety targeting the lysosome. The GILT-tag is derived from IGF-II, which is a high affinity ligand for the CI-MPR receptor, the same receptor on the cell surface that recognizes M6P-modified proteins. Binding of GILT-tagged therapeutic enzymes to the CI-MPR receptor targets the protein to the lysosome via the endocytic pathway. Thus, the pathway that GILT-tagged proteins take to the lysosome is identical to that taken by M6P-containing proteins, including the initial interaction with the CI-MPR receptor. In the case of ZyStor's candidate Pompe therapeutic ZC-701, the presence of a GILT tag on every ZC-701 enzyme molecule enables efficient lysosomal delivery of each ZC-701 molecule. In contrast, only a small fraction of Myozyme molecules contain sufficient M6P to target the M6P receptor. The Company believes that its proprietary GILT technology can provide a means of delivering therapeutic enzymes to a wide variety of clinically relevant cell types in LSD patients in addition to Pompe disease patients. By using a peptide tag instead of a M6P-labeled carbohydrate to engage the M6P receptor on diseased cells, GILT permits the removal or modification of the carbohydrate on GILT-modified enzymes without affecting uptake by the targeted cells, thereby rendering the enzyme invisible to the mannose receptor and other carbohydrate-binding receptors. Because less of the therapeutic enzyme is cleared by these receptors, more of the enzyme is available for uptake by target cells. It takes about a minute for a molecule to circulate from the heart to the body’s periphery and back. Therefore, even a modest five-minute increase in the half-life of an enzyme will provide five additional opportunities for the required enzyme to be taken up by the target tissues. GILT is designed to provide a functional enzyme to correct the metabolic process in the lysosomes of LSD patients. A target directing molecule, the GILT peptide tag, is embedded within the therapeutic enzyme to promote internalization into diseased cells. The internalization process is accomplished by the binding of the GILT tag to the M6P receptor found on the surface of the target cell, thereby facilitating endocytosis. Below illustrates the fundamental trafficking of these molecules. 
Click image for larger view. This illustration shows the interaction of ZyStor' modified enzyme/protein with the target cell surface receptor and the trafficking of these molecules to their intended destnation. The GILT receptor shown above is recycled to the cell surface via its natural pathway where as the therapeutic enzyme is delivered to the lysosome (target organelle). ZyStor believes that its GILT technology provides the following potential benefits: - the GILT tag has a high affinity for the M6P receptor that transports the therapeutic enzyme to the lysosome;
- use of the GILT tag in conjunction with the modification of carbohydrates results in more efficient delivery to the target cells, decreasing the amount and potentially the frequency of a therapeutic dose;
- because M6P does not need to be incorporated into the enzyme replacement therapy in order to achieve therapeutic uptake by the cells, several less expensive manufacturing alternatives are available;
- evidence exists that GILT may be able to deliver enzymes across the blood-brain barrier, which could potentially benefit LSD patients who often exhibit neurological pathologies that cannot be addressed by conventional enzyme replacement therapies; and
- because it is difficult to reproducibly obtain the identical oligosaccharide pattern when manufacturing recombinant proteins, the GILT technology should yield better batch-to-batch reproducibility.
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