Translating preclinical models of neuronal ceroid lipofuscinosis: progress and prospects

References

• Santavuori P. Neuronal ceroid-lipofuscinoses in childhood. Brain Dev. 1988;10(2):80–83.
   Google Scholar
• Bennett MJ, Rakheja D. The neuronal ceroid-lipofuscinoses. Dev Disabil Res Rev. 2013 Jun;17(3):254–259.
   Google Scholar
• Mole SE, Cotman SL. Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochim Biophys Acta. 2015 Oct;1852(10Pt B):2237–2241.
   Google Scholar
• Jalanko A, Braulke T. Neuronal ceroid lipofuscinoses. Biochim Biophys Acta. 2009 Apr;1793(4):697–709.
   Google Scholar
• Schulz A, Kohlschutter A, Mink J, et al. NCL diseases - clinical perspectives. Biochim Biophys Acta. 2013 Nov;1832(11):1801–1806.
   Google Scholar
• Goebel HH. The neuronal ceroid-lipofuscinoses. J Child Neurol. 1995 Nov;10(6):424–437.
   Google Scholar
• Haltia M. The neuronal ceroid-lipofuscinoses: from past to present. Biochim Biophys Acta. 2006 Oct;1762(10):850–856.
   Google Scholar
• Santorelli FM, Garavaglia B, Cardona F, et al. Molecular epidemiology of childhood neuronal ceroid-lipofuscinosis in Italy. Orphanet J Rare Dis. 2013 Feb;02(8):19.
   Google Scholar
• Schultz ML, Tecedor L, Chang M, et al. Clarifying lysosomal storage diseases. Trends Neurosci. 2011 Aug;34(8):401–410.
   Google Scholar
• Cotman SL, Karaa A, Staropoli JF, et al. Neuronal ceroid lipofuscinosis: impact of recent genetic advances and expansion of the clinicopathologic spectrum. Curr Neurol Neurosci Rep. 2013 Aug;13(8):366.
   Google Scholar
• Dolisca SB, Mehta M, Pearce DA, et al. Batten disease: clinical aspects, molecular mechanisms, translational science, and future directions. J Child Neurol. 2013 Sep;28(9):1074–1100.
   Google Scholar
• Williams RE, Aberg L, Autti T, et al. Diagnosis of the neuronal ceroid lipofuscinoses: an update. Biochim Biophys Acta. 2006 Oct;1762(10):865–872.
   Google Scholar
• Carcel-Trullols J, Kovacs AD, Pearce DA. Cell biology of the NCL proteins: what they do and don’t do. Biochim Biophys Acta. 2015 Oct;1852(10Pt B):2242–2255.
   Google Scholar
• Cooper JD, Tarczyluk MA, Nelvagal HR. Towards a new understanding of NCL pathogenesis. Biochim Biophys Acta. 2015 Oct;1852(10Pt B):2256–2261.
   Google Scholar
• Palmer DN, Barry LA, Tyynela J, et al. NCL disease mechanisms. Biochim Biophys Acta. 2013 Nov;1832(11):1882–1893.
   Google Scholar
• Geraets RD, Koh S, Hastings ML, et al. Moving towards effective therapeutic strategies for neuronal ceroid lipofuscinosis. Orphanet J Rare Dis. 2016;11:40.
   Google Scholar
• Haltia M, Goebel HH. The neuronal ceroid-lipofuscinoses: a historical introduction. Biochim Biophys Acta. 2013 Nov;1832(11):1795–1800.
   Google Scholar
• Warrier V, Vieira M, Mole SE. Genetic basis and phenotypic correlations of the neuronal ceroid lipofusinoses. Biochim Biophys Acta. 2013 Nov;1832(11):1827–1830.
   Google Scholar
• Kollmann K, Uusi-Rauva K, Scifo E, et al. Cell biology and function of neuronal ceroid lipofuscinosis-related proteins. Biochim Biophys Acta. 2013 Nov;1832(11):1866–1881.
   Google Scholar
• Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology. 2012 Jul 10;79(2):183–191.
   Google Scholar
• Augustine EF, Adams HR, Mink JW. Clinical trials in rare disease: challenges and opportunities. J Child Neurol. 2013 Sep;28(9):1142–1150.
   Google Scholar
• Bond M, Holthaus SM, Tammen I, et al. Use of model organisms for the study of neuronal ceroid lipofuscinosis. Biochim Biophys Acta. 2013 Nov;1832(11):1842–1865.
   Google Scholar
• Best HL, Neverman NJ, Wicky HE, et al. Characterisation of early changes in ovine CLN5 and CLN6 Batten disease neural cultures for the rapid screening of therapeutics. Neurobiol Dis. 2017 Apr;100:62–74.
   Google Scholar
• Shi Y, Inoue H, Wu JC, et al. Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov. 2017 Feb;16(2):115–130.
   Google Scholar
• Ebert AD, Svendsen CN. Human stem cells and drug screening: opportunities and challenges. Nat Rev Drug Discov. 2010 May;9(5):367–372.
   Google Scholar
• Cooper JD, Russell C, Mitchison HM. Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis. Biochim Biophys Acta. 2006 Oct;1762(10):873–889.
   Google Scholar
• Neverman NJ, Best HL, Hofmann SL, et al. Experimental therapies in the neuronal ceroid lipofuscinoses. Biochim Biophys Acta. 2015 Oct;1852(10Pt B):2292–2300.
   Google Scholar
• Mink JW, Augustine EF, Adams HR, et al. Classification and natural history of the neuronal ceroid lipofuscinoses. J Child Neurol. 2013 Sep;28(9):1101–1105.
   Google Scholar
• Palmer D. Reasons and responsibility for animal research. Vetscript. 2005;18(3):2–3.
   Google Scholar
• Levy N. The use of animal as models: ethical considerations. Int J Stroke. 2012 Jul;7(5):440–442.
   Google Scholar
• Gluck JP, Bell J. Ethical issues in the use of animals in biomedical and psychopharmocological research. Psychopharmacology (Berl). 2003 Dec;171(1):6–12.
   Google Scholar
• Jankowsky JL, Savonenko A, Schilling G, et al. Transgenic mouse models of neurodegenerative disease: opportunities for therapeutic development. Curr Neurol Neurosci Rep. 2002 Sep;2(5):457–464.
   Google Scholar
• Gama Sosa MA, De Gasperi R, Elder GA. Modeling human neurodegenerative diseases in transgenic systems. Hum Genet. 2012 Apr;131(4):535–563.
   Google Scholar
• Harvey BK, Richie CT, Hoffer BJ, et al. Transgenic animal models of neurodegeneration based on human genetic studies. J Neural Transm (Vienna). 2011 Jan;118(1):27–45.
   Google Scholar
• Nordgren A. Animal experimentation: pro and con arguments using the theory of evolution. Med Health Care Philos. 2002;5(1):23–31.
   Google Scholar
• Shacka JJ. Mouse models of neuronal ceroid lipofuscinoses: useful pre-clinical tools to delineate disease pathophysiology and validate therapeutics. Brain Res Bull. 2012 May 1;88(1):43–57.
   Google Scholar
• Bronson RT, Lake BD, Cook S, et al. Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten’s disease). Ann Neurol. 1993 Apr;33(4):381–385.
   Google Scholar
• Bronson RT, Donahue LR, Johnson KR, et al. Neuronal ceroid lipofuscinosis (nclf), a new disorder of the mouse linked to chromosome 9. Am J Med Genet. 1998 May 26;77(4):289–297.
   Google Scholar
• Bible E, Gupta P, Hofmann SL, et al. Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null mutant mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2004 Jul;16(2):346–359.
   Google Scholar
• Kielar C, Maddox L, Bible E, et al. Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2007 Jan;25(1):150–162.
   Google Scholar
• Pontikis CC, Cotman SL, MacDonald ME, et al. Thalamocortical neuron loss and localized astrocytosis in the Cln3Deltaex7/8 knock-in mouse model of Batten disease. Neurobiol Dis. 2005 Dec;20(3):823–836.
   Google Scholar
• Sleat DE, Wiseman JA, El-Banna M, et al. A mouse model of classical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration. J Neuroscience. 2004 Oct 13;24(41):9117–9126.
   Google Scholar
• Partanen S, Haapanen A, Kielar C, et al. Synaptic changes in the thalamocortical system of cathepsin D-deficient mice: a model of human congenital neuronal ceroid-lipofuscinosis. J Neuropathol Exp Neurol. 2008 Jan;67(1):16–29.
   Google Scholar
• Saftig P, Hetman M, Schmahl W, et al. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. Embo J. 1995 Aug 01;14(15):3599–3608.
   Google Scholar
• Kopra O, Vesa J, von Schantz C, et al. A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging. Hum Mol Genet. 2004 Dec 1;13(23):2893–2906.
   Google Scholar
• von Schantz C, Kielar C, Hansen SN, et al. Progressive thalamocortical neuron loss in Cln5 deficient mice: distinct effects in Finnish variant late infantile NCL. Neurobiol Dis. 2009 May;34(2):308–319.
   Google Scholar
• Cotman SL, Vrbanac V, Lebel LA, et al. Cln3(Deltaex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth. Hum Mol Genet. 2002 Oct 15;11(22):2709–2721.
   Google Scholar
• Bouchelion A, Zhang Z, Li Y, et al. Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype. Ann Clin Transl Neurol. 2014 Dec;1(12):1006–1023.
   Google Scholar
• Miller JN, Kovacs AD, Pearce DA. The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Hum Mol Genet. 2015 Jan 1;24(1):185–196.
   Google Scholar
• Geraets RD, Langin LM, Cain JT, et al. A tailored mouse model of CLN2 disease: a nonsense mutant for testing personalized therapies. PloS One. 2017;12(5):e0176526.
   Google Scholar
• Shyng C, Macauley SL, Dearborn JT, et al. Widespread expression of a membrane-tethered version of the soluble lysosomal enzyme palmitoyl protein thioesterase-1. JIMD Rep. 2017. doi: 10.1007/8904_2017_1. [Epub ahead of print].
   Google Scholar
• Damme M, Brandenstein L, Fehr S, et al. Gene disruption of Mfsd8 in mice provides the first animal model for CLN7 disease. Neurobiol Dis. 2014;65:12–24.
   Google Scholar
• Ahmed Z, Sheng H, Xu YF, et al. Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol. 2010 Jul;177(1):311–324.
   Google Scholar
• Schultheis PJ, Fleming SM, Clippinger AK, et al. Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited alpha-synuclein accumulation and age-dependent sensorimotor deficits. Hum Mol Genet. 2013 May 15;22(10):2067–2082.
   Google Scholar
• Gupta P, Soyombo AA, Atashband A, et al. Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proc Natl Acad Sci USA. 2001 Nov 20;98(24):13566–13571.
   Google Scholar
• Roberts MS, Macauley SL, Wong AM, et al. Combination small molecule PPT1 mimetic and CNS-directed gene therapy as a treatment for infantile neuronal ceroid lipofuscinosis. J Inherit Metab Dis. 2012 Sep;35(5):847–857.
   Google Scholar
• Wei H, Zhang Z, Saha A, et al. Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: partial rescue by resveratrol. Hum Mol Genet. 2011 Mar 15;20(6):1111–1121.
   Google Scholar
• Groh J, Berve K, Martini R. Fingolimod and teriflunomide attenuate neurodegeneration in mouse models of neuronal ceroid lipofuscinosis. Mol Therapy. 2017 May 13. pii: S1525-0016(17)30202-2. doi: 10.1016/j.ymthe.2017.04.021. [Epub ahead of print].
   Google Scholar
• Hu J, Lu JY, Wong AM, et al. Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis. Mol Genet Metab. 2012 Sep;107(1–2):213–221.
   Google Scholar
• Lu JY, Nelvagal HR, Wang L, et al. Intrathecal enzyme replacement therapy improves motor function and survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis. Mol Genet Metab. 2015 Sep–Oct;116(1–2):98–105.
   Google Scholar
• Tamaki SJ, Jacobs Y, Dohse M, et al. Neuroprotection of host cells by human central nervous system stem cells in a mouse model of infantile neuronal ceroid lipofuscinosis. Cell Stem Cell. 2009 Sep 4;5(3):310–319.
   Google Scholar
• Griffey M, Bible E, Vogler C, et al. Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2004 Jul;16(2):360–369.
   Google Scholar
• Griffey MA, Wozniak D, Wong M, et al. CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis. Mol Therapy. 2006 Mar;13(3):538–547.
   Google Scholar
• Macauley SL, Roberts MS, Wong AM, et al. Synergistic effects of central nervous system-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis. Ann Neurol. 2012 Jun;71(6):797–804.
   Google Scholar
• Shyng C, Nelvagal HR, Dearborn JT, et al. Synergistic effects of treating the spinal cord and brain in CLN1 disease. PNAS. 2017;114(29):E5920-E5929.
   Google Scholar
• Jalanko A, Vesa J, Manninen T, et al. Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons. Neurobiol Dis. 2005 Feb;18(1):226–241.
   Google Scholar
• Thada V, Miller JN, Kovacs AD, et al. Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1(R151X) mouse model of INCL. J Cell Mol Med. 2016 Feb;20(2):381–385.
   Google Scholar
• Sanders DN, Farias FH, Johnson GS, et al. A mutation in canine PPT1 causes early onset neuronal ceroid lipofuscinosis in a Dachshund. Mol Genet Metab. 2010 Aug;100(4):349–356.
   Google Scholar
• Kim K, Kleinman HK, Lee HJ, et al. Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders. Orphanet J Rare Dis. 2017 Jun 17;12(1):113.
   Google Scholar
• Passini MA, Dodge JC, Bu J, et al. Intracranial delivery of CLN2 reduces brain pathology in a mouse model of classical late infantile neuronal ceroid lipofuscinosis. J Neuroscience. 2006 Feb 1;26(5):1334–1342.
   Google Scholar
• Chang M, Cooper JD, Sleat DE, et al. Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Therapy. 2008 Apr;16(4):649–656.
   Google Scholar
• Meng Y, Sohar I, Sleat DE, et al. Effective intravenous therapy for neurodegenerative disease with a therapeutic enzyme and a peptide that mediates delivery to the brain. Mol Therapy. 2014 Mar;22(3):547–553.
   Google Scholar
• Xu S, Wang L, El-Banna M, et al. Large-volume intrathecal enzyme delivery increases survival of a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Therapy. 2011 Oct;19(10):1842–1848.
   Google Scholar
• Sondhi D, Peterson DA, Giannaris EL, et al. AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL. Gene Ther. 2005 Nov;12(22):1618–1632.
   Google Scholar
• Sondhi D, Peterson DA, Edelstein AM, et al. Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis. Exp Neurol. 2008 Sep;213(1):18–27.
   Google Scholar
• Sondhi D, Hackett NR, Peterson DA, et al. Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector. Mol Therapy. 2007 Mar;15(3):481–491.
   Google Scholar
• Awano T, Katz ML, O’Brien DP, et al. A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Mol Genet Metab. 2006 Nov;89(3):254–260.
   Google Scholar
• Katz ML, Coates JR, Sibigtroth CM, et al. Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). J Neurosci Res. 2014 Nov;92(11):1591–1598.
   Google Scholar
• Vuillemenot BR, Katz ML, Coates JR, et al. Intrathecal tripeptidyl-peptidase 1 reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis. Mol Genet Metab. 2011 Nov;104(3):325–337.
   Google Scholar
• Vuillemenot BR, Kennedy D, Cooper JD, et al. Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis. Mol Genet Metab. 2015 Feb;114(2):281–293.
   Google Scholar
• Katz ML, Tecedor L, Chen Y, et al. AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease. Sci Transl Med. 2015 Nov 11;7(313):313ra180.
   Google Scholar
• Mitchison HM, Bernard DJ, Greene ND, et al. Targeted disruption of the Cln3 gene provides a mouse model for Batten disease. Neurobiol Dis. 1999 Oct;6(5):321–334.
   Google Scholar
• Seehafer SS, Ramirez-Montealegre D, Wong AM, et al. Immunosuppression alters disease severity in juvenile Batten disease mice. J Neuroimmunol. 2011 Jan;230(1–2):169–172.
   Google Scholar
• Kovacs AD, Pearce DA. Attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile Batten disease. Exp Neurol. 2008 Jan;209(1):288–291.
   Google Scholar
• Kovacs AD, Saje A, Wong A, et al. Temporary inhibition of AMPA receptors induces a prolonged improvement of motor performance in a mouse model of juvenile Batten disease. Neuropharmacology. 2011 Feb–Mar;60(2–3):405–409.
   Google Scholar
• Kovacs AD, Saje A, Wong A, et al. Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease. Neuropharmacology. 2012 Jun 6;63:769–775.
   Google Scholar
• Katz ML, Shibuya H, Liu PC, et al. A mouse gene knockout model for juvenile ceroid-lipofuscinosis (Batten disease). J Neurosci Res. 1999 Aug 15;57(4):551–556.
   Google Scholar
• Aldrich A, Bosch ME, Fallet R, et al. Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3). Ann Neurol. 2016 Dec;80(6):909–923.
   Google Scholar
• Sondhi D, Scott EC, Chen A, et al. Partial correction of the CNS lysosomal storage defect in a mouse model of juvenile neuronal ceroid lipofuscinosis by neonatal CNS administration of an adeno-associated virus serotype rh.10 vector expressing the human CLN3 gene. Hum Gene Ther. 2014 Mar;25(3):223–239.
   Google Scholar
• Bosch ME, Aldrich A, Fallet R, et al. Self-complementary AAV9 gene delivery partially corrects pathology associated with juvenile neuronal ceroid lipofuscinosis (CLN3). J Neuroscience. 2016 Sep 14;36(37):9669–9682.
   Google Scholar
• Eliason SL, Stein CS, Mao Q, et al. A knock-in reporter model of Batten disease. J Neuroscience. 2007 Sep 12;27(37):9826–9834.
   Google Scholar
• Melville SA, Wilson CL, Chiang CS, et al. A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs. Genomics. 2005 Sep;86(3):287–294.
   Google Scholar
• Frugier T, Mitchell NL, Tammen I, et al. A new large animal model of CLN5 neuronal ceroid lipofuscinosis in Borderdale sheep is caused by a nucleotide substitution at a consensus splice site (c.571+1G>A) leading to excision of exon 3. Neurobiol Dis. 2008 Feb;29(2):306–315.
   Google Scholar
• Houweling PJ, Cavanagh JA, Palmer DN, et al. Neuronal ceroid lipofuscinosis in Devon cattle is caused by a single base duplication (c.662dupG) in the bovine CLN5 gene. Biochim Biophys Acta. 2006 Oct;1762(10):890–897.
   Google Scholar
• Katz ML, Farias FH, Sanders DN, et al. A missense mutation in canine CLN6 in an Australian shepherd with neuronal ceroid lipofuscinosis. J Biomed Biotechnol. 2011;2011:198042.
   Google Scholar
• Tammen I, Houweling PJ, Frugier T, et al. A missense mutation (c.184C>T) in ovine CLN6 causes neuronal ceroid lipofuscinosis in Merino sheep whereas affected South Hampshire sheep have reduced levels of CLN6 mRNA. Biochim Biophys Acta. 2006 Oct;1762(10):898–905.
   Google Scholar
• Broom MF, Zhou C, Broom JE, et al. Ovine neuronal ceroid lipofuscinosis: a large animal model syntenic with the human neuronal ceroid lipofuscinosis variant CLN6. J Med Genet. 1998 Sep;35(9):717–721.
   Google Scholar
• Faller KM, Bras J, Sharpe SJ, et al. The Chihuahua dog: a new animal model for neuronal ceroid lipofuscinosis CLN7 disease? J Neurosci Res. 2016 Apr;94(4):339–347.
   Google Scholar
• Elger B, Schneider M, Winter E, et al. Optimized synthesis of AMPA receptor antagonist ZK 187638 and neurobehavioral activity in a mouse model of neuronal ceroid lipofuscinosis. ChemMedChem. 2006 Oct;1(10):1142–1148.
   Google Scholar
• Katz ML, Khan S, Awano T, et al. A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun. 2005 Feb 11;327(2):541–547.
   Google Scholar
• Follo C, Ozzano M, Mugoni V, et al. Knock-down of cathepsin D affects the retinal pigment epithelium, impairs swim-bladder ontogenesis and causes premature death in zebrafish. PloS One. 2011;6(7):e21908.
   Google Scholar
• Shevtsova Z, Garrido M, Weishaupt J, et al. CNS-expressed cathepsin D prevents lymphopenia in a murine model of congenital neuronal ceroid lipofuscinosis. Am J Pathol. 2010 Jul;177(1):271–279.
   Google Scholar
• Awano T, Katz ML, O’Brien DP, et al. A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis. Mol Genet Metab. 2006 Apr;87(4):341–348.
   Google Scholar
• Tyynela J, Sohar I, Sleat DE, et al. A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration. EMBO J. 2000 Jun 15;19(12):2786–2792.
   Google Scholar
• Kayasuga Y, Chiba S, Suzuki M, et al. Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res. 2007 Dec 28;185(2):110–118.
   Google Scholar
• Wohlke A, Philipp U, Bock P, et al. A one base pair deletion in the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrier. PLoS Genet. 2011 Oct;7(10):e1002304.
   Google Scholar
• Shyng C, Sands MS. Astrocytosis in infantile neuronal ceroid lipofuscinosis: friend or foe? Biochem Soc Trans. 2014 Oct;42(5):1282–1285.
   Google Scholar
• Bosch ME, Kielian T. Neuroinflammatory paradigms in lysosomal storage diseases. Front Neurosci. 2015;9:417.
   Google Scholar
• Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci. 2010 Jul;13(7):805–811.
   Google Scholar
• Mitchison HM, Lim MJ, Cooper JD. Selectivity and types of cell death in the neuronal ceroid lipofuscinoses. Brain Pathology. 2004 Jan;14(1):86–96.
   Google Scholar
• Kovacs AD, Weimer JM, Pearce DA. Selectively increased sensitivity of cerebellar granule cells to AMPA receptor-mediated excitotoxicity in a mouse model of Batten disease. The Batten Mouse Model Consortium [corrected]. Neurobiol Dis. 2006 Jun;22(3):575–585.
   Google Scholar
• Finn R, Kovacs AD, Pearce DA. Altered glutamate receptor function in the cerebellum of the Ppt1(-/-) mouse, a murine model of infantile neuronal ceroid lipofuscinosis. J Neurosci Res. 2012 Feb;90(2):367–375.
   Google Scholar
• Cooper JD. The neuronal ceroid lipofuscinoses: the same, but different? Biochem Soc Trans. 2010 Dec;38(6):1448–1452.
   Google Scholar
• Oswald MJ, Palmer DN, Kay GW, et al. Glial activation spreads from specific cerebral foci and precedes neurodegeneration in presymptomatic ovine neuronal ceroid lipofuscinosis (CLN6). Neurobiol Dis. 2005 Oct;20(1):49–63.
   Google Scholar
• Galvin N, Vogler C, Levy B, et al. A murine model of infantile neuronal ceroid lipofuscinosis-ultrastructural evaluation of storage in the central nervous system and viscera. Pediatr Dev Pathol. 2008 May-Jun;11(3):185–192.
   Google Scholar
• Staropoli JF, Haliw L, Biswas S, et al. Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system. PloS One. 2012;7(6):e38310.
   Google Scholar
• Guo S. Linking genes to brain, behavior and neurological diseases: what can we learn from zebrafish? Genes Brain Behav. 2004 Apr;3(2):63–74.
   Google Scholar
• Mahmood F, Fu S, Cooke J, et al. A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation. Brain. 2013 May;136(Pt(5)):1488–1507.
   Google Scholar
• Wager K, Zdebik AA, Fu S, et al. Neurodegeneration and epilepsy in a zebrafish model of CLN3 disease (Batten disease). PloS One. 2016;11(6):e0157365.
   Google Scholar
• Solchenberger B, Russell C, Kremmer E, et al. Granulin knock out zebrafish lack frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis pathology. PloS One. 2015;10(3):e0118956.
   Google Scholar
• Hagen LO. Lipid dystrophic changes in the central nervous system in dogs. Acta Pathol Microbiol Scand. 1953;33(1):22–35.
   Google Scholar
• Weber K, Pearce DA. Large animal models for Batten disease: a review. J Child Neurol. 2013 Sep;28(9):1123–1127.
   Google Scholar
• Sanders DN, Kanazono S, Wininger FA, et al. A reversal learning task detects cognitive deficits in a Dachshund model of late-infantile neuronal ceroid lipofuscinosis. Genes Brain Behav. 2011 Oct;10(7):798–804.
   Google Scholar
• Palmer DN, Neverman NJ, Chen JZ, et al. Recent studies of ovine neuronal ceroid lipofuscinoses from BARN, the Batten Animal Research Network. Biochim Biophys Acta. 2015 Oct;1852(10Pt B):2279–2286.
   Google Scholar
• Perentos N, Martins AQ, Cumming RJ, et al. An EEG investigation of sleep homeostasis in healthy and CLN5 Batten disease affected sheep. J Neuroscience. 2016 Aug 03;36(31):8238–8249.
   Google Scholar
• Perentos N, Martins AQ, Watson TC, et al. Translational neurophysiology in sheep: measuring sleep and neurological dysfunction in CLN5 Batten disease affected sheep. Brain. 2015 Apr;138(Pt(4):862–874.
   Google Scholar
• Hirz M, Drogemuller M, Schanzer A, et al. Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenlandische Dachsbracke dog. Mol Genet Metab. 2017 Mar;120(3):269–277.
   Google Scholar
• Guo J, O’Brien DP, Mhlanga-Mutangadura T, et al. A rare homozygous MFSD8 single-base-pair deletion and frameshift in the whole genome sequence of a Chinese Crested dog with neuronal ceroid lipofuscinosis. BMC Vet Res. 2015 Jan 03;10:960.
   Google Scholar
• Kolicheski A, Johnson GS, O’Brien DP, et al. Australian cattle dogs with neuronal ceroid lipofuscinosis are homozygous for a CLN5 nonsense mutation previously identified in border collies. J Vet Intern Med. 2016 Jul;30(4):1149–1158.
   Google Scholar
• Kolicheski A, Barnes Heller HL, Arnold S, et al. Homozygous PPT1 splice donor mutation in a Cane Corso dog with neuronal ceroid lipofuscinosis. J Vet Intern Med. 2017 Jan;31(1):149–157.
   Google Scholar
• Fratantoni JC, Hall CW, Neufeld EF. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science. 1968 Nov 1;162(3853):570–572.
   Google Scholar
• Neufeld EF. Enzyme replacement therapy - a brief history. In: Mehta A, Beck M, Sunder-Plassmann G, editor Fabry disease: perspectives from 5 years of FOS. Oxford PharmaGenesis. 2006.
   Google Scholar
• Wong AM, Rahim AA, Waddington SN, et al. Current therapies for the soluble lysosomal forms of neuronal ceroid lipofuscinosis. Biochem Soc Trans. 2010 Dec;38(6):1484–1488.
   Google Scholar
• Sands MS, Davidson BL. Gene therapy for lysosomal storage diseases. Mol Therapy. 2006 May;13(5):839–849.
   Google Scholar
• Desnick RJ. Enzyme replacement and beyond. J Inherit Metab Dis. 2001 Apr;24(2):251–265.
   Google Scholar
• Desnick RJ. Enzyme replacement and enhancement therapies for lysosomal diseases. J Inherit Metab Dis. 2004;27(3):385–410.
   Google Scholar
• Begley DJ, Pontikis CC, Scarpa M. Lysosomal storage diseases and the blood-brain barrier. Current Pharmaceutical Design. 2008;14(16):1566–1580.
   Google Scholar
• Augustine EF, Mink JW. Enzyme replacement in neuronal storage disorders in the pediatric population. Curr Treat Options Neurol. 2013 Oct;15(5):634–651.
   Google Scholar
• Beck M. New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy. Hum Genet. 2007 Mar;121(1):1–22.
   Google Scholar
• Lee K, Jin X, Zhang K, et al. A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease. Glycobiology. 2003 Apr;13(4):305–313.
   Google Scholar
• Sun B, Bird A, Young SP, et al. Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance. Am J Hum Genet. 2007 Nov;81(5):1042–1049.
   Google Scholar
• Wraith JE, Clarke LA, Beck M, et al. Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J Pediatr. 2004 May;144(5):581–588.
   Google Scholar
• Schulz A, Specchio N, Gissen P, et al. Long-term safety and efficacy of intracerebroventricular enzyme replacement therapy with cerliponase alfa in children with CLN2 disease: interim results from an ongoing multicenter, multinational extension study. Mol Genet Metab. 2017;120(1):S120.
   Google Scholar
• Bavarsad Shahripour R, Harrigan MR, Alexandrov AV. N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities. Brain Behav. 2014 Mar;4(2):108–122.
   Google Scholar
• Zhang Z, Butler JD, Levin SW, et al. Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med. 2001 Apr;7(4):478–484.
   Google Scholar
• Gavin M, Wen GY, Messing J, et al. Substrate reduction therapy in four patients with milder CLN1 mutations and juvenile-onset batten disease using cysteamine bitartrate. JIMD Rep. 2013;11:87–92.
   Google Scholar
• Levin SW, Baker EH, Zein WM, et al. Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study. Lancet Neurol. 2014 Aug;13(8):777–787.
   Google Scholar
• Kim SJ, Zhang Z, Lee YC, et al. Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. Hum Mol Genet. 2006 May 15;15(10):1580–1586.
   Google Scholar
• Wei H, Kim SJ, Zhang Z, et al. Mukherjee AB. ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones. Hum Mol Genet. 2008 Feb 15;17(4):469–477.
   Google Scholar
• Zhang Z, Lee YC, Kim SJ, et al. Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Hum Mol Genet. 2006 Jan 15;15(2):337–346.
   Google Scholar
• Yoon DH, Kwon OY, Mang JY, et al. Protective potential of resveratrol against oxidative stress and apoptosis in Batten disease lymphoblast cells. Biochem Biophys Res Commun. 2011 Oct 14;414(1):49–52.
   Google Scholar
• Saha A, Sarkar C, Singh SP, et al. The blood-brain barrier is disrupted in a mouse model of infantile neuronal ceroid lipofuscinosis: amelioration by resveratrol. Hum Mol Genet. 2012 May 15;21(10):2233–2244.
   Google Scholar
• Kousi M, Lehesjoki AE, Mole SE. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat. 2012 Jan;33(1):42–63.
   Google Scholar
• Brooks DA, Muller VJ, Hopwood JJ. Stop-codon read-through for patients affected by a lysosomal storage disorder. Trends Mol Med. 2006 Aug;12(8):367–373.
   Google Scholar
• Lee HL, Dougherty JP. Pharmaceutical therapies to recode nonsense mutations in inherited diseases. Pharmacol Ther. 2012 Nov;136(2):227–266.
   Google Scholar
• Sarkar C, Zhang Z, Mukherjee AB. Stop codon read-through with PTC124 induces palmitoyl-protein thioesterase-1 activity, reduces thioester load and suppresses apoptosis in cultured cells from INCL patients. Mol Genet Metab. 2011 Nov;104(3):338–345.
   Google Scholar
• Chattopadhyay S, Ito M, Cooper JD, et al. An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Hum Mol Genet. 2002 Jun 1;11(12):1421–1431.
   Google Scholar
• Chattopadhyay S, Kriscenski-Perry E, Wenger DA, et al. An autoantibody to GAD65 in sera of patients with juvenile neuronal ceroid lipofuscinoses. Neurology. 2002 Dec 10;59(11):1816–1817.
   Google Scholar
• Lim MJ, Alexander N, Benedict JW, et al. IgG entry and deposition are components of the neuroimmune response in Batten disease. Neurobiol Dis. 2007 Feb;25(2):239–251.
   Google Scholar
• Castaneda JA, Lim MJ, Cooper JD, et al. Immune system irregularities in lysosomal storage disorders. Acta Neuropathol. 2008 Feb;115(2):159–174.
   Google Scholar
• Pontikis CC, Cella CV, Parihar N, et al. Late onset neurodegeneration in the Cln3-/- mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation. Brain Res. 2004 Oct 15;1023(2):231–242.
   Google Scholar
• Groh J, Kuhl TG, Ip CW, et al. Immune cells perturb axons and impair neuronal survival in a mouse model of infantile neuronal ceroid lipofuscinosis. Brain. 2013 Apr;136(Pt 4):1083–1101.
   Google Scholar
• Sarkar C, Chandra G, Peng S, et al. Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic implications for INCL. Nat Neurosci. 2013 Nov;16(11):1608–1617.
   Google Scholar
• Palmieri M, Pal R, Nelvagal HR, et al. mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases. Nat Commun. 2017 Feb 06;8:14338.
   Google Scholar
• Neufeld EF, Fratantoni JC. Inborn errors of mucopolysaccharide metabolism. Science. 1970 Jul 10;169(3941):141–146.
   Google Scholar
• Armitage JO. Bone marrow transplantation. N Engl J Med. 1994 Mar 24;330(12):827–838.
   Google Scholar
• Deeg HJ, Shulman HM, Albrechtsen D, et al. Batten’s disease: failure of allogeneic bone marrow transplantation to arrest disease progression in a canine model. Clin Genet. 1990 Apr;37(4):264–270.
   Google Scholar
• Lake BD, Steward CG, Oakhill A, et al. Bone marrow transplantation in late infantile Batten disease and juvenile Batten disease. Neuropediatrics. 1997 Feb;28(1):80–81.
   Google Scholar
• Lonnqvist T, Vanhanen SL, Vettenranta K, et al. Hematopoietic stem cell transplantation in infantile neuronal ceroid lipofuscinosis. Neurology. 2001 Oct 23;57(8):1411–1416.
   Google Scholar
• Shihabuddin LS, Cheng SH. Neural stem cell transplantation as a therapeutic approach for treating lysosomal storage diseases. Neurotherapeutics. 2011 Oct;8(4):659–667.
   Google Scholar
• Tamaki S, Eckert K, He D, et al. Engraftment of sorted/expanded human central nervous system stem cells from fetal brain. J Neurosci Res. 2002 Sep 15;69(6):976–986.
   Google Scholar
• Uchida N, Buck DW, He D, et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA. 2000 Dec 19;97(26):14720–14725.
   Google Scholar
• Bowers WJ, Breakefield XO, Sena-Esteves M. Genetic therapy for the nervous system. Hum Mol Genet. 2011 Apr 15;20(R1):R28–41.
   Google Scholar
• Verma IM, Weitzman MD. Gene therapy: twenty-first century medicine. Annu Rev Biochem. 2005;74:711–738.
   Google Scholar
• Aronovich EL, Hackett PB. Lysosomal storage disease: gene therapy on both sides of the blood-brain barrier. Mol Genet Metab. 2015 Feb;114(2):83–93.
   Google Scholar
• Zaiss AK, Muruve DA. Immune responses to adeno-associated virus vectors. Curr Gene Ther. 2005 Jun;5(3):323–331.
   Google Scholar
• Swain GP, Prociuk M, Bagel JH, et al. Adeno-associated virus serotypes 9 and rh10 mediate strong neuronal transduction of the dog brain. Gene Ther. 2014 Jan;21(1):28–36.
   Google Scholar
• Aschauer DF, Kreuz S, Rumpel S. Analysis of transduction efficiency, tropism and axonal transport of AAV serotypes 1, 2, 5, 6, 8 and 9 in the mouse brain. PloS One. 2013;8(9):e76310.
   Google Scholar
• Dayton RD, Wang DB, Klein RL. The advent of AAV9 expands applications for brain and spinal cord gene delivery. Expert Opin Biol Ther. 2012 Jun;12(6):757–766.
   Google Scholar
• Foust KD, Nurre E, Montgomery CL, et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009 Jan;27(1):59–65.
   Google Scholar
• Schuster DJ, Dykstra JA, Riedl MS, et al. Biodistribution of adeno-associated virus serotype 9 (AAV9) vector after intrathecal and intravenous delivery in mouse. Front Neuroanat. 2014;8:42.
   Google Scholar
• Huda F, Konno A, Matsuzaki Y, et al. Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model. Mol Ther Methods Clin Dev. 2014;1:14032.
   Google Scholar
• Gray SJ, Matagne V, Bachaboina L, et al. Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol Therapy. 2011 Jun;19(6):1058–1069.
   Google Scholar
• Sands MS. Considerations for the treatment of infantile neuronal ceroid lipofuscinosis (infantile Batten disease). J Child Neurol. 2013 Sep;28(9):1151–1158.
   Google Scholar
• Griffey M, Macauley SL, Ogilvie JM, et al. AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis. Mol Therapy. 2005 Sep;12(3):413–421.
   Google Scholar
• Sondhi D, Johnson L, Purpura K, et al. Long-term expression and safety of administration of AAVrh.10hCLN2 to the brain of rats and nonhuman primates for the treatment of late infantile neuronal ceroid lipofuscinosis. Hum Gene Ther Methods. 2012 Oct;23(5):324–335.
   Google Scholar
• Worgall S, Sondhi D, Hackett NR, et al. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther. 2008 May;19(5):463–474.
   Google Scholar
• Tuxworth RI, Vivancos V, O’Hare MB, et al. Interactions between the juvenile Batten disease gene, CLN3, and the Notch and JNK signalling pathways. Hum Mol Genet. 2009 Feb 15; 18(4):667–678.
   Google Scholar
• Ostergaard JR, Rasmussen TB, Molgaard H. Cardiac involvement in juvenile neuronal ceroid lipofuscinosis (Batten disease). Neurology. 2011 Apr 05;76(14):1245–1251.
   Google Scholar
• Macauley SL, Wong AM, Shyng C, et al. An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis. J Neuroscience. 2014 Sep 24;34(39):13077–13082.
   Google Scholar
• Anderson GW, Goebel HH, Simonati A. Human pathology in NCL. Biochim Biophys Acta. 2013 Nov;1832(11):1807–1826.
   Google Scholar
• Tomiyasu H, Takahashi W, Ohta T, et al. [An autopsy case of juvenile neuronal ceroid-lipofuscinosis with dilated cardiomyopathy]. Rinsho Shinkeigaku. 2000 Apr;40(4):350–357.
   Google Scholar
• Hu C, Busuttil RW, Lipshutz GS. RH10 provides superior transgene expression in mice when compared with natural AAV serotypes for neonatal gene therapy. J Gene Med. 2010 Sep;12(9):766–778.
   Google Scholar
• Fietz M, AlSayed M, Burke D, et al. Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): expert recommendations for early detection and laboratory diagnosis. Mol Genet Metab. 2016 Sep;119(1–2):160–167.
   Google Scholar
• Marshall FJ, de Blieck EA, Mink JW, et al. A clinical rating scale for Batten disease: reliable and relevant for clinical trials. Neurology. 2005 Jul 26;65(2):275–279.
   Google Scholar
• Dyke JP, Voss HU, Sondhi D, et al. Assessing disease severity in late infantile neuronal ceroid lipofuscinosis using quantitative MR diffusion-weighted imaging. AJNR Am J Neuroradiol. 2007 Aug;28(7):1232–1236.
   Google Scholar
• Steinfeld R, Heim P, von Gregory H, et al. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet. 2002 Nov 01;112(4):347–354.
   Google Scholar