Chronic Enzyme Replacement to the Brain of a Late Infantile Neuronal Ceroid Lipofuscinosis Mouse Has Differential Effects on Phenotypes of Disease

Abstract

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal inherited neurodegenerative disease caused by loss of lysosomal protease tripeptidyl peptidase 1 (TPP1). We have investigated the effects of chronic intrathecal (IT) administration using enzyme replacement therapy (ERT) to the brain of an LINCL mouse model, in which locomotor function declines dramatically prior to early death. Median lifespan was significantly extended from 126 days to >259 days when chronic IT treatment was initiated before the onset of disease. While treated animals lived longer and showed little sign of locomotor dysfunction as measured by stride length, some or all (depending on regimen) still died prematurely. One explanation is that cerebrospinal fluid (CSF)-mediated delivery may not deliver TPP1 to all brain regions. Morphological studies support this, showing delivery of TPP1 to ventral, but not deeper and dorsal regions. When IT treatment is initiated in severely affected LINCL mice, lifespan was extended modestly in most but dramatically extended in approximately one-third of the cohort. Treatment improved locomotor function in these severely compromised animals after it had declined to the point at which animals normally die. This indicates that some pathology in LINCL is reversible and does not simply reflect neuronal death.

A Basic ApoE-Based Peptide Mediator to Deliver Proteins across the Blood-Brain Barrier: Long-Term Efficacy, Toxicity, and Mechanism

“…It is worth noting that in a recent study from our laboratory, 19 fluorescent rhTPP1 was delivered to the brain via the cerebrospinal fluid (CSF) using an intrathecal injection. Here, overall distribution of rhTPP1 was quite uneven, with the most efficient delivery to ventral surfaces of the brain and very poor or undetectable delivery to dorsal and deep brain regions, such as the hippocampus.…”

“…Sections were prepared for whole-slide imaging as described. 19 Biotin staining was conducted as described. 34…”

“…described previously in detail. 19 Whole-slide images were acquired using an Olympus VS120 whole-slide scanner equipped with an Olympus XM10 cooled monochrome 14-bit camera. NHS-sulfobiotin staining was conducted as described.…”

Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses

“…Intrathecal injection of TPP1 slows down CLN2 disease in mice and humans. Flupirtine and aromatic carbamate derivatives antiapoptotic properties provide the basis for use as potential therapies in NCL disease.…”

Inducible transgenic expression of tripeptidyl peptidase 1 in a mouse model of late-infantile neuronal ceroid lipofuscinosis

“…This could indicate either triggering of pathophysiological pathways that cannot be reversed by restoration of TPP1, or accumulated storage material in a subset of cell types that becomes refractory to clearance. We have also conducted enzyme replacement therapy (ERT) in the LINCL mouse [ 10 , 11 ] and again found that earlier treatment was again more effective. However, an unexpected finding was that a subset of highly-symptomatic animals responded well to treatment, with significantly increased lifespan [ 10 ].…”