Intrathecal tripeptidyl-peptidase 1 reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis

Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis

“…In a previous study, severe infusion associated reactions (IARs) were observed after repeat intracisternal injections of rhTPP1 in TPP1-null Dachshunds [32]. None of the animals in the present study that received bolus injections exhibited such reactions.…”

“…These reactions were less severe than those observed following repeat bolus intrathecal injection in these animals [32]. The lower severity is likely due to the reduced systemic exposure resulting from infusion as compared with bolus injection.…”

“…Previous studies have demonstrated rhTPP1 pharmacological effects when delivered to the CSF in murine [5] and canine [32] disease models. CNS administration of enzymes in animal models has resulted in minimal safety findings [8,10,30].…”

“…Affected animals display progressive neurological decline requiring euthanasia at 10-11 months old [15,26]. We have previously demonstrated that repeat intrathecal (IT) injection results in brain distribution of active rhTPP1 and reduced accumulation of lysosomal storage [32]. However, the relatively rapid administration of rhTPP1 associated with IT injections resulted in infusion associated reactions (IARs) consisting of a hypersensitivity response with clinical signs of facial swelling, hyperemia, urticarial, vomiting, hypotension, and tachycardia.…”

Gemfibrozil and Fenofibrate, Food and Drug Administration-approved Lipid-lowering Drugs, Up-regulate Tripeptidyl-peptidase 1 in Brain Cells via Peroxisome Proliferator-activated Receptor α

“…Studies using adeno-associated virus and other viral vectors expressing recombinant TPP1 demonstrate widespread expression of TPP1, and treatment of Cln2-targeted mice with these recombinant vectors show slowing of disease-associated pathology and an increase in survival in mutant mice (36 -38). However, levels of TPPI activity achievable by adeno-associated virus-mediated gene therapy can vary and depend on various critical parameters, and there is considerable doubt whether similar effects can be achieved in humans (36,39). Nevertheless, restoration of activity at even low levels could prove helpful for most lysosomal storage diseases, where restoration of even Ͻ10% of normal activity may have therapeutic benefits (40).…”