The neuronal ceroid lipofuscinoses (NCLs) are a group of closely related hereditary neurodegenerative disorders which affect infants, children and adults, and which occur at a frequency of between 2 and 4 in 100,000 live births. Most forms of NCL afflict children and their early symptoms and disease progression tend to be similar. Initial diagnosis is frequently based upon visual problems, behavioral changes and seizures. Progression is reflected by a decline in mental abilities, increasingly severe and untreatable seizures, blindness and loss of motor skills while further progression can result in dementia or a vegetative state. There is no effective treatment for NCL and all childhood forms are eventually fatal. Several forms of NCL are differentiated according to age of onset, clinical pathology and genetic linkage. These include infantile NCL (INCL, CLN1), classical late infantile NCL (LINCL, CLN2), juvenile NCL (JNCL, CLN3) adult NCL (CLN4), two variant forms of LINCL (CLN5 and CLN6) and possibly other atypical forms.
The CLN2 gene and protein (described in U.S. Ser. No. 08/931,608, filed Sep. 16, 1997, and Sleat et al. (1997) Science 277:1802-1805), when mutated, result in the autosomal recessive disease classical late infantile neuronal ceroid lipofuscinosis (LINCL, OMIM 204500). CLN2 encodes the protein lysosomal enzyme tripeptidyl peptidase I (also called CLN2 protein, CLN2 gene product, TPP-1, EC3.4.14.9) (Sleat et al., Vines and Warburton (1999), FEBS Lett. 443 131-135) which is a 46 KDa lysomal protein that is absent or mutated in LINCL. In its absence, storage material whose major identifiable component is mitochondrial ATP synthase subunit c accumulates in the lysosomes of affected patients in neurons and other cell types (Palmer et al. (1995) Am. J. Med. Genet. 57:260-265). There is a need to develop therapeutic applications, based on CLN2, for treatment of LINCL and related diseases. Currently, there is no effective treatment for the disease and death typically occurs between ages 6 and 15 (Mole (1993) Neurobiol. Dis. 5:237-303).
Enzyme replacement therapy is a desirable treatment for lysosomal storage diseases such as LINCL that are characterized by a deficient amount of functional CLN2 protein in the affected cells. In enzyme replacement therapy recombinant (or natural) enzyme is administered to the affected cells to correct the metabolic defect, an approach that has proven successful for Gaucher's disease. Administration of glucocerebrosidase has proved remarkably effective in treating many patients with Gaucher's disease (Brady, R. O. and Barton, N. W. (1994) Biochem Med Metab Biol 52, 1-9), and there are clinical trials ongoing for a number of other lysosomal storage disorders (Schiffmann et al. (2000) Proc Natl Acad Sci USA 97, 365-370; Bijvoet et al. (1999) Hum Mol Genet. 8, 2145-2153; Chen, Y. T. and Amalfitano, A. (2000) Mol Med Today 6, 245-251; Downs-Kelly et al. J. Mol. Neurosci. (2000); Kaye (2001) in Current Treatment Options in Neurology 3:249-256; Kakkis et al. (2001) Mol. Genet. Metab. 72:199-208; Byers et al. (2000) Pediatr. Res. 47:743-749; Brady and Schiffman (2000) JAMA 284:2771-2775; Vogler et al. (1999) Pediatr. Res. 45:838-844; Zirzow et al. (1999) Neurochem. Res. 24:301-305; Platt and Butters ((1998) Biochem. Pharmacol. 56:421-430; Crawley et al. (1997) J. Clin. Invest. 99:651-662; Brady and Barton (1997) Lipids Mar. 31 Suppl. S137-139; Barton et al. (1993) New Eng. J. Med. 328:1564, 1567, 1568).