Intraventricular Enzyme Replacement Improves Disease Phenotypes in a Mouse Model of Late Infantile Neuronal Ceroid Lipofuscinosis

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, USA.
Molecular Therapy (Impact Factor: 6.23). 05/2008; 16(4):649-56. DOI: 10.1038/mt.2008.9
Source: PubMed


Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive neurodegenerative disease caused by mutations in CLN2, which encodes the lysosomal protease tripeptidyl peptidase 1 (TPP1). LINCL is characterized clinically by progressive motor and cognitive decline, and premature death. Enzyme-replacement therapy (ERT) is currently available for lysosomal storage diseases affecting peripheral tissues, but has not been used in patients with central nervous system (CNS) involvement. Enzyme delivery through the cerebrospinal fluid is a potential alternative route to the CNS, but has not been studied for LINCL. In this study, we identified relevant neuropathological and behavioral hallmarks of disease in a mouse model of LINCL and correlated those findings with tissues from LINCL patients. Subsequently, we tested if intraventricular delivery of TPP1 to the LINCL mouse was efficacious. We found that infusion of recombinant human TPP1 through an intraventricular cannula led to enzyme distribution in several regions of the brain of treated mice. In vitro activity assays confirm increased TPP1 activity throughout the rostral-caudal extent of the brain. Importantly, treated mice showed attenuated neuropathology, and decreased resting tremor relative to vehicle-treated mice. This data demonstrates that intraventricular enzyme delivery to the CNS is feasible and may be of therapeutic value.

Download full-text


Available from: Seng H. Cheng,
24 Reads
  • Source
    • "Therefore, CLN2 disease is amenable to TPP1 enzyme replacement therapy (ERT). Because large molecules such as TPP1 cannot cross the bloodebrain barrier, delivery of the enzyme to the brain has been achieved through administration of TPP1 pro-enzyme by infusion into the cerebrospinal fluid (CSF) in mouse and dog (Chang et al., 2008; Vuillemenot et al., 2011). In the Dachshund CLN2 disease model, we have previously shown that this route of TPP1 administration results in widespread distribution of the active enzyme in many structures of the brain and in reduction in the accumulation of neuronal lysosomal storage material that is characteristic of this disease (Vuillemenot et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Late-infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. This fatal pediatric disease is caused by mutations in the CLN2 gene which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Utilizing a TAP1-/- Dachshund model of CLN2 disease, studies were conducted to assess the effects of TPP1 enzyme replacement administered directly to the CNS on disease progression. Recombinant human TPP1 (rhTPP1) or artificial cerebrospinal fluid vehicle was administered to CLN2-affected dogs via infusion into the CSF. Untreated and vehicle treated affected dogs exhibited progressive declines in pupillary light reflexes (PLRs) and electroretinographic (ERG) responses to light stimuli. Studies were undertaken to determine whether CSF administration of rhTPP1 alters progression of the PLR and ERG deficits in the canine model. rhTPP1 administration did not inhibit the decline in ERG responses, as rhTPP1 treated, vehicle treated, and untreated dogs all exhibited similar progressive and profound declines in ERG amplitudes. However, in some of the dogs treated with rhTPP1 there were substantial delays in the appearance and progression of PLR deficits compared with untreated or vehicle treated affected dogs. These findings indicate that CSF administration of TPP1 can attenuate functional impairment of neural pathways involved in mediating the PLR but does not prevent loss of retinal responses detectable with ERG. (C) 2014 The Authors. Published by Elsevier Ltd.
    Experimental Eye Research 08/2014; 125:164-172. DOI:10.1016/j.exer.2014.06.008 · 2.71 Impact Factor
  • Source
    • "Recently, ERT have also been developed for the treatment of Late Infantile Neuronal Ceroid Lipofuscinosis (NCL) [52] [53]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lysosomal storage diseases (LSDs) are a group of rare genetic multisystemic disorders, resulting in deficient lysosomal activity. These pathologies are characterized by progressive accumulation of storage material within the lysosomes, ultimately leading to organ dysfunctions. LSDs patient's clinical outcomes have significantly improved, since the advent of enzyme replacement therapy (ERT). ERT is approved worldwide for 6 LSDs: Gaucher disease, Fabry disease, Mucopolysaccharidosis types I, II, and VI, and Pompe disease. The efficacy and safety of ERT for LSDs has been confirmed by extensive clinical trials, however therapy with infused protein is life-long and disease progression is still observed in treated patients. Obstacles to successful ERT, such as immune reactions against the infused enzyme, miss-targeting of recombinant enzymes, and difficult delivery to crucial tissues (i.e. brain and bone), determine the need for further research, in order to ameliorate therapeutic strategies. Viral gene therapy, stem cell based therapy, pharmacological chaperones and could be considered essential tools for future improvement of recombinant enzyme trafficking and targeting. This review will discuss recent patents and new strategic approaches for enzyme delivery to highlight the most relevant aspects, concerning next generation LSDs treatment.
    Recent Patents on Endocrine Metabolic & Immune Drug Discovery 01/2014; 8(1). DOI:10.2174/1872214808666140115111350
  • Source
    • "Studies in mouse and dog models of mucopolysaccharidosis IIIA also revealed that the strategy was effective in ameliorating neuropathology and improving clinical signs in affected animals.23,24 Other studies in mice with the LSDs Krabbe disease and late infantile neuronal ceroid lipofuscinosis demonstrated that delivery of recombinant lysosomal enzymes into the CSF was efficacious in reducing disease pathology and neurological signs and symptoms.25,26 Thus, the principle that provision of enzyme into the CSF is beneficial for LSDs is gaining considerable traction. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fetal brain-directed gene addition represents an under-appreciated tool for investigating novel therapeutic approaches in animal models of central nervous system diseases with early prenatal onset. Choroid plexuses (CPs) are specialized neuroectoderm-derived structures that project into the brain's ventricles, produce cerebrospinal fluid (CSF), and regulate CSF biochemical composition. Targeting the CP may be advantageous for adeno-associated viral (AAV) gene therapy for central nervous system disorders due to its immunoprivileged location and slow rate of epithelial turnover. Yet the capacity of AAV vectors to transduce CP has not been delineated precisely. We performed intracerebroventricular injections of recombinant AAV serotype 5-green fluorescent protein (rAAV5-GFP) or rAAV9-GFP in embryonic day 15 (E15) embryos of CD-1 and C57BL/6 pregnant mice and quantified the percentages of GFP expression in CP epithelia (CPE) from lateral and fourth ventricles on E17, postnatal day 2 (P2), and P22. AAV5 was selective for CPE and showed significantly higher transduction efficiency in C57BL/6 mice (P = 0.0128). AAV9 transduced neurons and glial cells in both the mouse strains, in addition to CPE. We documented GFP expression in CPE on E17, within just 48 hours of rAAV administration to the fetal lateral ventricle, and expression by both the serotypes persisted at P130. Our results indicate that prenatal administration of rAAV5 and rAAV9 enables rapid, robust, and sustained transduction of mouse CPE and buttress the rationale for experimental therapeutics targeting the CP.Molecular Therapy-Nucleic Acids (2013) 2, e101; doi:10.1038/mtna.2013.27; published online 25 June 2013.
    Molecular Therapy - Nucleic Acids 06/2013; 2(6):e101. DOI:10.1038/mtna.2013.27 · 4.51 Impact Factor
Show more