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  • Review Article
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Therapeutic landscape for Batten disease: current treatments and future prospects

Abstract

Batten disease (also known as neuronal ceroid lipofuscinoses) constitutes a family of devastating lysosomal storage disorders that collectively represent the most common inherited paediatric neurodegenerative disorders worldwide. Batten disease can result from mutations in 1 of 13 genes. These mutations lead to a group of diseases with loosely overlapping symptoms and pathology. Phenotypically, patients with Batten disease have visual impairment and blindness, cognitive and motor decline, seizures and premature death. Pathologically, Batten disease is characterized by lysosomal accumulation of autofluorescent storage material, glial reactivity and neuronal loss. Substantial progress has been made towards the development of effective therapies and treatments for the multiple forms of Batten disease. In 2017, cerliponase alfa (Brineura), a tripeptidyl peptidase enzyme replacement therapy, became the first globally approved treatment for CLN2 Batten disease. Here, we provide an overview of the promising therapeutic avenues for Batten disease, highlighting current FDA-approved clinical trials and prospective future treatments.

Key points

  • The FDA approval of the enzyme replacement therapy cerliponase alfa (Brineura) for the treatment of CLN2 Batten disease is an important milestone in Batten disease therapy.

  • Promising results from preclinical research indicate that gene therapy — particularly approaches that use adeno-associated virus — represents a promising treatment option for patients in the near future.

  • Many of the preclinical strategies being explored for the treatment of one form of Batten disease could have applications across multiple subtypes of Batten disease and even other lysosomal storage disorders.

  • Investigators now recognize that a single treatment might not be sufficient to halt disease progression and are exploring combinatorial approaches to tackle multiple aspects of Batten disease progression.

  • A battery of new preclinical and clinical tools have been developed that facilitate effective therapy development in Batten disease, enabling an unprecedented acceleration in drug discovery for these fatal disorders.

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Fig. 1: Gene therapy and enzyme replacement therapy strategies in Batten disease.

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References

  1. Zeman, W. & Dyken, P. Neuronal ceroid-lipofuscinosis (Batten’s disease): relationship to amaurotic family idiocy? Pediatrics 44, 570–583 (1969).

    CAS  PubMed  Google Scholar 

  2. Aldrich, A. & Kielian, T. Central nervous system fibrosis is associated with fibrocyte-like infiltrates. Am. J. Pathol. 179, 2952–2962 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Rider, J. A. & Rider, D. L. Batten disease: past, present, and future. Am. J. Med. Genet. Suppl. 5, 21–26 (1988).

    CAS  PubMed  Google Scholar 

  4. Santavuori, P. Neuronal ceroid-lipofuscinoses in childhood. Brain Dev. 10, 80–83 (1988).

    CAS  PubMed  Google Scholar 

  5. Jalanko, A. & Braulke, T. Neuronal ceroid lipofuscinoses. Biochim. Biophys. Acta 1793, 697–709 (2009).

    CAS  PubMed  Google Scholar 

  6. Stengel, O. C. Beretning om et maerkeligt Sygdomstilfaelde hos fire Sødskende I Nærheden af Röraas. Eyr 1, 347–352 (1826).

    Google Scholar 

  7. Batten, F. E. Cerebral degeneration with symmetrical changes in the maculae in two members of a family. Trans. Ophthalmol. Soc. UK 23, 386–390 (1903).

    Google Scholar 

  8. Adams, H. R. & Mink, J. W., University of Rochester Batten Center Study Group. Neurobehavioral features and natural history of juvenile neuronal ceroid lipofuscinosis (Batten disease). J. Child Neurol. 28, 1128–1136 (2013).

    PubMed  PubMed Central  Google Scholar 

  9. Haltia, M. The neuronal ceroid-lipofuscinoses: from past to present. Biochim. Biophys. Acta 1762, 850–856 (2006).

    CAS  PubMed  Google Scholar 

  10. Goebel, H. H., Zeman, W. & Pilz, H. Ultrastructural investigations of peripheral nerves in neuronal ceroid-lipofuscinoses (NCL). J. Neurol. 213, 295–303 (1976).

    CAS  PubMed  Google Scholar 

  11. Haltia, M., Rapola, J. & Santavuori, P. Infantile type of so-called neuronal ceroid-lipofuscinosis. Histological and electron microscopic studies. Acta Neuropathol. 26, 157–170 (1973).

    CAS  PubMed  Google Scholar 

  12. Anderson, G. W., Goebel, H. H. & Simonati, A. Human pathology in NCL. Biochim. Biophys. Acta 1832, 1807–1826 (2013).

    CAS  PubMed  Google Scholar 

  13. Goebel, H. H. Fingerprint inclusions in non-vacuolated lymphocytes in juvenile neuronal ceroid-lipofuscinosis. Clin. Neuropathol. 4, 210–213 (1985).

    CAS  PubMed  Google Scholar 

  14. Nijssen, P. C. et al. Autosomal dominant adult neuronal ceroid lipofuscinosis: a novel form of NCL with granular osmiophilic deposits without palmitoyl protein thioesterase 1 deficiency. Brain Pathol. 13, 574–581 (2003).

    CAS  PubMed  Google Scholar 

  15. Siintola, E. et al. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129, 1438–1445 (2006).

    PubMed  Google Scholar 

  16. Sandbank, U. Congenital amaurotic idiocy. Pathol. Eur. 3, 226–229 (1968).

    CAS  PubMed  Google Scholar 

  17. Humphreys, S., Lake, B. D. & Scholtz, C. L. Congenital amaurotic idiocy — a pathological, histochemical, biochemical and ultrastructural study. Neuropathol. Appl. Neurobiol. 11, 475–484 (1985).

    CAS  PubMed  Google Scholar 

  18. Barohn, R. J., Dowd, D. C. & Kagan-Hallet, K. S. Congenital ceroid-lipofuscinosis. Pediatr. Neurol. 8, 54–59 (1992).

    CAS  PubMed  Google Scholar 

  19. Meyer, S. et al. Congenital CLN disease in two siblings. Wien. Med. Wochenschr. 165, 210–213 (2015).

    PubMed  Google Scholar 

  20. Norman, R. M. & Wood, N. A congenital form of amaurotic family idiocy. J. Neurol. Psychiatry 4, 175–190 (1941).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Garborg, I., Torvik, A., Hals, J., Tangsrud, S. E. & Lindemann, R. Congenital neuronal ceroid lipofuscinosis. A case report. Acta Pathol. Microbiol. Immunol. Scand. A 95, 119–125 (1987).

    CAS  PubMed  Google Scholar 

  22. Brown, N. J., Corner, B. D. & Dodgson, M. C. A second case in the same family of congenital familial cerebral lipoidosis resembling amaurotic family idiocy. Arch. Dis. Child 29, 48–54 (1954).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Fritchie, K. et al. Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10). Acta Neuropathol. 117, 201–208 (2009).

    PubMed  Google Scholar 

  24. Goebel, H. H. et al. Prenatal diagnosis of infantile neuronal ceroid-lipofuscinosis: a combined electron microscopic and molecular genetic approach. Brain Dev. 17, 83–88 (1995).

    CAS  PubMed  Google Scholar 

  25. Lerner, T. J. et al. Isolation of a novel gene underlying Batten disease, CLN3. Cell 82, 949–957 (1995).

    Google Scholar 

  26. Weimer, J. M., Kriscenski-Perry, E., Elshatory, Y. & Pearce, D. A. The neuronal ceroid lipofuscinoses: mutations in different proteins result in similar disease. Neuromolecular Med. 1, 111–124 (2002).

    CAS  PubMed  Google Scholar 

  27. Williams, R. E. & Mole, S. E. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology 79, 183–191 (2012).

    PubMed  Google Scholar 

  28. Kohan, R. et al. An integrated strategy for the diagnosis of neuronal ceroid lipofuscinosis types 1 (CLN1) and 2 (CLN2) in eleven Latin American patients. Clin. Genet. 76, 372–382 (2009).

    CAS  PubMed  Google Scholar 

  29. Kohan, R. et al. The neuronal ceroid lipofuscinoses program: a translational research experience in Argentina. Biochim. Biophys. Acta 1852, 2301–2311 (2015).

    CAS  PubMed  Google Scholar 

  30. Steinfeld, R. et al. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am. J. Med. Genet. 112, 347–354 (2002).

    PubMed  Google Scholar 

  31. de Blieck, E. A. et al. Methodology of clinical research in rare diseases: development of a research program in juvenile neuronal ceroid lipofuscinosis (JNCL) via creation of a patient registry and collaboration with patient advocates. Contemp. Clin. Trials 35, 48–54 (2013).

    PubMed  PubMed Central  Google Scholar 

  32. Mink, J. W., Augustine, E. F., Adams, H. R., Marshall, F. J. & Kwon, J. M. Classification and natural history of the neuronal ceroid lipofuscinoses. J. Child Neurol. 28, 1101–1105 (2013).

    PubMed  PubMed Central  Google Scholar 

  33. Nickel, M. et al. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child Adolesc. Health 2, 582–590 (2018).

    PubMed  PubMed Central  Google Scholar 

  34. Simonati, A. et al. Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5. Dev. Med. Child Neurol. 59, 815–821 (2017).

    PubMed  Google Scholar 

  35. Dolisca, S. B., Mehta, M., Pearce, D. A., Mink, J. W. & Maria, B. L. Batten disease: clinical aspects, molecular mechanisms, translational science, and future directions. J. Child Neurol. 28, 1074–1100 (2013).

    PubMed  PubMed Central  Google Scholar 

  36. Goebel, H. H. & Wisniewski, K. E. Current state of clinical and morphological features in human NCL. Brain Pathol. 14, 61–69 (2004).

    CAS  PubMed  Google Scholar 

  37. Williams, R. E. et al. Diagnosis of the neuronal ceroid lipofuscinoses: an update. Biochim. Biophys. Acta 1762, 865–872 (2006).

    CAS  PubMed  Google Scholar 

  38. Radke, J., Stenzel, W. & Goebel, H. H. Human NCL neuropathology. Biochim. Biophys. Acta 1852, 2262–2266 (2015).

    CAS  PubMed  Google Scholar 

  39. Vesa, J. et al. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376, 584–587 (1995).

    CAS  PubMed  Google Scholar 

  40. Greaves, J. & Chamberlain, L. H. Palmitoylation-dependent protein sorting. J. Cell Biol. 176, 249–254 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kakela, R., Somerharju, P. & Tyynela, J. Analysis of phospholipid molecular species in brains from patients with infantile and juvenile neuronal-ceroid lipofuscinosis using liquid chromatography-electrospray ionization mass spectrometry. J. Neurochem. 84, 1051–1065 (2003).

    CAS  PubMed  Google Scholar 

  42. Lyly, A. et al. Deficiency of the INCL protein Ppt1 results in changes in ectopic F1-ATP synthase and altered cholesterol metabolism. Hum. Mol. Genet. 17, 1406–1417 (2008).

    CAS  PubMed  Google Scholar 

  43. Ahtiainen, L. et al. Palmitoyl protein thioesterase 1 (PPT1) deficiency causes endocytic defects connected to abnormal saposin processing. Exp. Cell Res. 312, 1540–1553 (2006).

    CAS  PubMed  Google Scholar 

  44. Kielar, C. et al. Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease. Hum. Mol. Genet. 18, 4066–4080 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Kim, S. J. et al. Palmitoyl protein thioesterase-1 deficiency impairs synaptic vesicle recycling at nerve terminals, contributing to neuropathology in humans and mice. J. Clin. Invest. 118, 3075–3086 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Das, A. K. et al. Molecular genetics of palmitoyl-protein thioesterase deficiency in the US. J. Clin. Invest. 102, 361–370 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Das, A. K., Lu, J. Y. & Hofmann, S. L. Biochemical analysis of mutations in palmitoyl-protein thioesterase causing infantile and late-onset forms of neuronal ceroid lipofuscinosis. Hum. Mol. Genet. 10, 1431–1439 (2001).

    CAS  PubMed  Google Scholar 

  48. Kohan, R. et al. Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America. Gene 516, 114–121 (2013).

    CAS  PubMed  Google Scholar 

  49. Kay, G. W., Verbeek, M. M., Furlong, J. M., Willemsen, M. A. A. P. & Palmer, D. N. Neuropeptide changes and neuroactive amino acids in CSF from humans and sheep with neuronal ceroid lipofuscinoses (NCLs, Batten disease). Neurochem. Int. 55, 783–788 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Breedveld, G. J. et al. A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15. J. Med. Genet. 41, 858–866 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sun, Y. et al. Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease). Hum. Mutat. 34, 706–713 (2013).

    CAS  PubMed  Google Scholar 

  52. Mole, S. E., Williams, R. E. & Goebel, H. H. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 6, 107–126 (2005).

    PubMed  Google Scholar 

  53. Ku, C. A. et al. Detailed clinical phenotype and molecular genetic findings in CLN3-associated isolated retinal degeneration. JAMA Ophthalmol. 135, 749–760 (2017).

    PubMed  PubMed Central  Google Scholar 

  54. Santavuori, P., Rapola, J., Sainio, K. & Raitta, C. A variant of Jansky-Bielschowsky disease. Neuropediatrics 13, 135–141 (1982).

    CAS  PubMed  Google Scholar 

  55. Santavuori, P. et al. The spectrum of Jansky-Bielschowsky disease. Neuropediatrics 22, 92–96 (1991).

    CAS  PubMed  Google Scholar 

  56. Xin, W. et al. CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL. Neurology 74, 565–571 (2010).

    CAS  PubMed  Google Scholar 

  57. Pineda-Trujillo, N. et al. A CLN5 mutation causing an atypical neuronal ceroid lipofuscinosis of juvenile onset. Neurology 64, 740–742 (2005).

    CAS  PubMed  Google Scholar 

  58. Mancini, C. et al. Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations. J. Neurol. 262, 173–178 (2015).

    CAS  PubMed  Google Scholar 

  59. Haines, J. L. et al. Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis. Neurogenetics 1, 217–222 (1998).

    CAS  PubMed  Google Scholar 

  60. Berkovic, S. F., Carpenter, S., Andermann, F., Andermann, E. & Wolfe, L. S. Kufs’ disease: a critical reappraisal. Brain 111, 27–62 (1988).

    PubMed  Google Scholar 

  61. Fietz, M. et al. Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): expert recommendations for early detection and laboratory diagnosis. Mol. Genet. Metab. 119, 160–167 (2016).

    CAS  PubMed  Google Scholar 

  62. Lake, B. D., Young, E. P. & Winchester, B. G. Prenatal diagnosis of lysosomal storage diseases. Brain Pathol. 8, 133–149 (1998).

    CAS  PubMed  Google Scholar 

  63. Munroe, P. B. et al. Prenatal diagnosis of Batten’s disease. Lancet 347, 1014–1015 (1996).

    CAS  PubMed  Google Scholar 

  64. Chow, C. W., Borg, J., Billson, V. R. & Lake, B. D. Fetal tissue involvement in the late infantile type of neuronal ceroid lipofuscinosis. Prenat. Diagn. 13, 833–841 (1993).

    CAS  PubMed  Google Scholar 

  65. Rapola, J., Salonen, R., Ammala, P. & Santavuori, P. Prenatal diagnosis of infantile neuronal ceroid-lipofuscinosis, INCL: morphological aspects. J. Inherit. Metab. Dis. 16, 349–352 (1993).

    CAS  PubMed  Google Scholar 

  66. Martin, J. J. & de Groote, C. Involvement of the skin in late infantile and juvenile amaurotic idiocies (neuronal ceroid-lipofuscinoses). Pathol. Eur. 9, 263–272 (1974).

    CAS  PubMed  Google Scholar 

  67. Ceuterick, C. & Martin, J. J. Diagnostic role of skin or conjunctival biopsies in neurological disorders. An update. J. Neurol. Sci. 65, 179–191 (1984).

    CAS  PubMed  Google Scholar 

  68. Brett, E. M. & Lake, B. D. Reassessment of rectal approach to neuropathology in childhood: review of 307 biopsies over 11 years. Arch. Dis. Child 50, 753–762 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Rapola, J., Santavuori, P. & Savilahti, E. Suction biopsy of rectal mucosa in the diagnosis of infantile and juvenile types of neuronal ceroid lipofuscinoses. Hum. Pathol. 15, 352–360 (1984).

    CAS  PubMed  Google Scholar 

  70. Ceuterick-de Groote, C. & Martin, J. J. Extracerebral biopsy in lysosomal and peroxisomal disorders. Ultrastructural findings. Brain Pathol. 8, 121–132 (1998).

    CAS  PubMed  Google Scholar 

  71. Nita, D. A., Mole, S. E. & Minassian, B. A. Neuronal ceroid lipofuscinoses. Epilept. Disord. 18, 73–88 (2016).

    Google Scholar 

  72. Anderson, G., Smith, V. V., Malone, M. & Sebire, N. J. Blood film examination for vacuolated lymphocytes in the diagnosis of metabolic disorders; retrospective experience of more than 2,500 cases from a single centre. J. Clin. Pathol. 58, 1305–1310 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Goebel, H. H. The neuronal ceroid-lipofuscinoses. J. Child Neurol. 10, 424–437 (1995).

    CAS  PubMed  Google Scholar 

  74. Mole, S. E. & Williams, R. E. Neuronal ceroid-lipofuscinoses. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1428 (updated 1 Aug 2013).

  75. Junaid, M. A., Sklower Brooks, S., Wisniewski, K. E. & Pullarkat, R. K. A novel assay for lysosomal pepstatin-insensitive proteinase and its application for the diagnosis of late-infantile neuronal ceroid lipofuscinosis. Clin. Chim. Acta 281, 169–176 (1999).

    CAS  PubMed  Google Scholar 

  76. van Diggelen, O. P. et al. A rapid fluorogenic palmitoyl-protein thioesterase assay: pre- and postnatal diagnosis of INCL. Mol. Genet. Metab. 66, 240–244 (1999).

    PubMed  Google Scholar 

  77. Voznyi, Y. V. et al. A new simple enzyme assay for pre- and postnatal diagnosis of infantile neuronal ceroid lipofuscinosis (INCL) and its variants. J. Med. Genet. 36, 471–474 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Vines, D. J. & Warburton, M. J. Classical late infantile neuronal ceroid lipofuscinosis fibroblasts are deficient in lysosomal tripeptidyl peptidase I. FEBS Lett. 443, 131–135 (1999).

    CAS  PubMed  Google Scholar 

  79. Sohar, I., Lin, L. & Lobel, P. Enzyme-based diagnosis of classical late infantile neuronal ceroid lipofuscinosis: comparison of tripeptidyl peptidase I and pepstatin-insensitive protease assays. Clin. Chem. 46, 1005–1008 (2000).

    CAS  PubMed  Google Scholar 

  80. Partanen, S. et al. A replacement of the active-site aspartic acid residue 293 in mouse cathepsin D affects its intracellular stability, processing and transport in HEK-293 cells. Biochem. J. 369, 55–62 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Mole, S. E. & Cotman, S. L. Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochim. Biophys. Acta 1852, 2237–2241 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Patiño, L. C. et al. Exome sequencing is an efficient tool for variant late-infantile neuronal ceroid lipofuscinosis molecular diagnosis. PLOS ONE 9, e109576 (2014).

    PubMed  PubMed Central  Google Scholar 

  83. Braak, H. & Goebel, H. H. Loss of pigment-laden stellate cells: a severe alteration of the isocortex in juvenile neuronal ceroid-lipofuscinosis. Acta Neuropathol. 42, 53–57 (1978).

    CAS  PubMed  Google Scholar 

  84. Braak, H. & Goebel, H. H. Pigmentoarchitectonic pathology of the isocortex in juvenile neuronal ceroid-lipofuscinosis: axonal enlargements in layer IIIab and cell loss in layer V. Acta Neuropathol. 46, 79–83 (1979).

    CAS  PubMed  Google Scholar 

  85. Haltia, M. The neuronal ceroid-lipofuscinoses. J. Neuropathol. Exp. Neurol. 62, 1–13 (2003).

    PubMed  Google Scholar 

  86. Haltia, M., Herva, R., Suopanki, J., Baumann, M. & Tyynela, J. Hippocampal lesions in the neuronal ceroid lipofuscinoses. Eur. J. Paediatr. Neurol. 5 (Suppl. A), 209–211 (2001).

    PubMed  Google Scholar 

  87. Tyynela, J., Cooper, J. D., Khan, M. N., Shemilts, S. J. & Haltia, M. Hippocampal pathology in the human neuronal ceroid-lipofuscinoses: distinct patterns of storage deposition, neurodegeneration and glial activation. Brain Pathol. 14, 349–357 (2004).

    PubMed  Google Scholar 

  88. Tyynela, J., Suopanki, J., Santavuori, P., Baumann, M. & Haltia, M. Variant late infantile neuronal ceroid-lipofuscinosis: pathology and biochemistry. J. Neuropathol. Exp. Neurol. 56, 369–375 (1997).

    CAS  PubMed  Google Scholar 

  89. Collins, J., Holder, G. E., Herbert, H. & Adams, G. G. Batten disease: features to facilitate early diagnosis. Br. J. Ophthalmol. 90, 1119–1124 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Spalton, D. J., Taylor, D. S. & Sanders, M. D. Juvenile Batten’s disease: an ophthalmological assessment of 26 patients. Br. J. Ophthalmol. 64, 726–732 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Birch, D. G. Retinal degeneration in retinitis pigmentosa and neuronal ceroid lipofuscinosis: an overview. Mol. Genet. Metab. 66, 356–366 (1999).

    CAS  PubMed  Google Scholar 

  92. Elleder, M. & Tyynela, J. Incidence of neuronal perikaryal spheroids in neuronal ceroid lipofuscinoses (Batten disease). Clin. Neuropathol. 17, 184–189 (1998).

    CAS  PubMed  Google Scholar 

  93. Carcel-Trullols, J., Kovacs, A. D. & Pearce, D. A. Cell biology of the NCL proteins: what they do and don’t do. Biochim. Biophys. Acta 1852, 2242–2255 (2015).

    CAS  PubMed  Google Scholar 

  94. Bond, M., Holthaus, S. M., Tammen, I., Tear, G. & Russell, C. Use of model organisms for the study of neuronal ceroid lipofuscinosis. Biochim. Biophys. Acta 1832, 1842–1865 (2013).

    CAS  PubMed  Google Scholar 

  95. Courtine, G. et al. Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans? Nat. Med. 13, 561–566 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. van der Worp, H. B. et al. Can animal models of disease reliably inform human studies? PLOS Med. 7, e1000245 (2010).

    PubMed  PubMed Central  Google Scholar 

  97. Kovacs, A. D. & Pearce, D. A. Finding the most appropriate mouse model of juvenile CLN3 (Batten) disease for therapeutic studies: the importance of genetic background and gender. Dis. Model. Mech. 8, 351–361 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Shacka, J. J. Mouse models of neuronal ceroid lipofuscinoses: useful pre-clinical tools to delineate disease pathophysiology and validate therapeutics. Brain Res. Bull. 88, 43–57 (2012).

    CAS  PubMed  Google Scholar 

  99. Augustine, E. F. et al. Short-term administration of mycophenolate is well-tolerated in CLN3 disease (juvenile neuronal ceroid lipofuscinosis). JIMD Rep. https://doi.org/10.1007/8904_2018_113 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Levin, S. W. et al. Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study. Lancet Neurol. 13, 777–787 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Selden, N. R. et al. Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis. J. Neurosurg. Pediatr. 11, 643–652 (2013).

    PubMed  Google Scholar 

  102. Weber, K. & Pearce, D. A. Large animal models for Batten disease: a review. J. Child Neurol. 28, 1123–1127 (2013).

    PubMed  PubMed Central  Google Scholar 

  103. Beraldi, R., Mdaki, K., Kovacs, A. D. & Pearce, D. A. Generation of a Juvenile Batten disease porcine model [abstract O15]. Presented at the 15th International Conference of Neuronal Ceroid Lipofuscinosis (Batten disease) in Boston, MA, USA (2016).

  104. McBride, J. L. et al. Discovery of a CLN7 model of Batten disease in non-human primates. Neurobiol. Dis. 119, 65–78 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Katz, M. L. et al. A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem. Biophys. Res. Commun. 327, 541–547 (2005).

    CAS  PubMed  Google Scholar 

  106. Melville, S. A. et al. A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs. Genomics 86, 287–294 (2005).

    CAS  PubMed  Google Scholar 

  107. Tammen, I. 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 1762, 898–905 (2006).

    CAS  PubMed  Google Scholar 

  108. Tyynela, J. et al. Congenital ovine neuronal ceroid lipofuscinosis — a cathepsin D deficiency with increased levels of the inactive enzyme. Eur. J. Paediatr. Neurol. 5 (Suppl. A), 43–45 (2001).

    PubMed  Google Scholar 

  109. Wei, X. et al. Initial experience with a juvenile sheep model for evaluation of the pediatric intracorporeal ventricular assist devices [corrected]. ASAIO J. 59, 75–80 (2013).

    PubMed  PubMed Central  Google Scholar 

  110. Sorby-Adams, A. J., Vink, R. & Turner, R. J. Large animal models of stroke and traumatic brain injury as translational tools. Am. J. Physiol. Regul. Integr. Comp. Physiol. 315, R165–R190 (2018).

    PubMed  Google Scholar 

  111. Swindle, M. M., Makin, A., Herron, A. J., Clubb, F. J. Jr & Frazier, K. S. Swine as models in biomedical research and toxicology testing. Vet. Pathol. 49, 344–356 (2012).

    CAS  PubMed  Google Scholar 

  112. Phillips, K. A. et al. Why primate models matter. Am. J. Primatol. 76, 801–827 (2014).

    PubMed  PubMed Central  Google Scholar 

  113. Jelsing, J. et al. The postnatal development of neocortical neurons and glial cells in the Gottingen minipig and the domestic pig brain. J. Exp. Biol. 209, 1454–1462 (2006).

    PubMed  Google Scholar 

  114. Pond, W. G. et al. Perinatal ontogeny of brain growth in the domestic pig. Proc. Soc. Exp. Biol. Med. 223, 102–108 (2000).

    CAS  PubMed  Google Scholar 

  115. Beraldi, R. et al. A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease. Hum. Mol. Genet. 24, 6473–6484 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Welsh, M. J., Rogers, C. S., Stoltz, D. A., Meyerholz, D. K. & Prather, R. S. Development of a porcine model of cystic fibrosis. Trans. Am. Clin. Climatol. Assoc. 120, 149–162 (2009).

    PubMed  PubMed Central  Google Scholar 

  117. Stoltz, D. A. et al. Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth. Sci. Transl Med. 2, 29ra31 (2010).

    PubMed  PubMed Central  Google Scholar 

  118. White, K. A. et al. A porcine model of neurofibromatosis type 1 (NF1) that mimics the human disease. JCI Insight 3, 120402 (2018).

    PubMed  Google Scholar 

  119. Chattopadhyay, S. et al. An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Hum. Mol. Genet. 11, 1421–1431 (2002).

    CAS  PubMed  Google Scholar 

  120. Andrews, W. J., Magee, A. G., Gardiner, P. V., Fleming, I. & Morris, T. C. Paroxysmal nocturnal haemoglobinuria and diabetes mellitus. Ulster Med. J. 59, 84–86 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Hu, J. 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. 107, 213–221 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Lu, J. Y., Hu, J. & Hofmann, S. L. Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis. Mol. Genet. Metab. 99, 374–378 (2010).

    CAS  PubMed  Google Scholar 

  123. Lu, J. Y. et al. Intrathecal enzyme replacement therapy improves motor function and survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis. Mol. Genet. Metab. 116, 98–105 (2015).

    CAS  PubMed  Google Scholar 

  124. Chattopadhyay, S., Kriscenski-Perry, E., Wenger, D. A. & Pearce, D. A. An autoantibody to GAD65 in sera of patients with juvenile neuronal ceroid lipofuscinoses. Neurology 59, 1816–1817 (2002).

    PubMed  Google Scholar 

  125. Chang, M. et al. Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol. Ther. 16, 649–656 (2008).

    CAS  PubMed  Google Scholar 

  126. Young, P. P., Fantz, C. R. & Sands, M. S. VEGF disrupts the neonatal blood-brain barrier and increases life span after non-ablative BMT in a murine model of congenital neurodegeneration caused by a lysosomal enzyme deficiency. Exp. Neurol. 188, 104–114 (2004).

    CAS  PubMed  Google Scholar 

  127. Neuwelt, E. A. et al. Delivery of hexosaminidase A to the cerebrum after osmotic modification of the blood—brain barrier. Proc. Natl Acad. Sci. USA 78, 5838–5841 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Saraiva, C. et al. Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases. J. Control. Release 235, 34–47 (2016).

    CAS  PubMed  Google Scholar 

  129. da Fonseca, A. C. et al. The impact of microglial activation on blood-brain barrier in brain diseases. Front. Cell. Neurosci. 8, 362 (2014).

    PubMed  PubMed Central  Google Scholar 

  130. Rite, I., Machado, A., Cano, J. & Venero, J. L. Blood-brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons. J. Neurochem. 101, 1567–1582 (2007).

    CAS  PubMed  Google Scholar 

  131. Vuillemenot, B. R. et al. Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis. Mol. Genet. Metab. 114, 281–293 (2015).

    CAS  PubMed  Google Scholar 

  132. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01907087 (2018).

  133. Schulz, A. et al. Study of intraventricular cerliponase alfa for CLN2 disease. N. Engl. J. Med. 378, 1898–1907 (2018).

    CAS  PubMed  Google Scholar 

  134. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02485899 (2018).

  135. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02678689 (2018).

  136. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02963350 (2017).

  137. Worgall, S. et al. Neurological deterioration in late infantile neuronal ceroid lipofuscinosis. Neurology 69, 521 (2007).

    CAS  PubMed  Google Scholar 

  138. Lobel, U. et al. Volumetric description of brain atrophy in neuronal ceroid lipofuscinosis 2: supratentorial gray matter shows uniform disease progression. AJNR Am. J. Neuroradiol. 37, 1938–1943 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00976352 (2018).

  140. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01474343 (2014).

  141. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02053064 (2017).

  142. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02716246 (2018).

  143. Sawamoto, K., Chen, H. H., Almeciga-Diaz, C. J., Mason, R. W. & Tomatsu, S. Gene therapy for mucopolysaccharidoses. Mol. Genet. Metab. 123, 59–68 (2018).

    CAS  PubMed  Google Scholar 

  144. Colella, P., Ronzitti, G. & Mingozzi, F. Emerging issues in AAV-mediated in vivo gene therapy. Mol. Ther. Methods Clin. Dev. 8, 87–104 (2018).

    CAS  PubMed  Google Scholar 

  145. Murlidharan, G., Samulski, R. J. & Asokan, A. Biology of adeno-associated viral vectors in the central nervous system. Front. Mol. Neurosci. 7, 76 (2014).

    PubMed  PubMed Central  Google Scholar 

  146. Griffey, M. 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. 16, 360–369 (2004).

    CAS  PubMed  Google Scholar 

  147. Griffey, M. A. et al. CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis. Mol. Ther. 13, 538–547 (2006).

    CAS  PubMed  Google Scholar 

  148. Katz, M. L. 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. 7, 313ra180 (2015).

    PubMed  PubMed Central  Google Scholar 

  149. Opie, S. R. et al. Identification of amino acid residues in the capsid proteins of adeno-associated virus type 2 that contribute to heparan sulfate proteoglycan binding. J. Virol. 77, 6995–7006 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Cabrera-Salazar, M. A. et al. Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease. Mol. Ther. 15, 1782–1788 (2007).

    CAS  PubMed  Google Scholar 

  151. Sondhi, D. et al. Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector. Mol. Ther. 15, 481–491 (2007).

    CAS  PubMed  Google Scholar 

  152. Mietzsch, M., Broecker, F., Reinhardt, A., Seeberger, P. H. & Heilbronn, R. Differential adeno-associated virus serotype-specific interaction patterns with synthetic heparins and other glycans. J. Virol. 88, 2991–3003 (2014).

    PubMed  PubMed Central  Google Scholar 

  153. Sondhi, D. 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. 25, 223–239 (2014).

    CAS  PubMed  Google Scholar 

  154. Macauley, S. L. et al. An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis. J. Neurosci. 34, 13077–13082 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Shyng, C. et al. Synergistic effects of treating the spinal cord and brain in CLN1 disease. Proc. Natl Acad. Sci. USA 114, E5920–E5929 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Kleine Holthaus, S. M. et al. Prevention of photoreceptor cell loss in a Cln6nclf mouse model of Batten disease requires CLN6 gene transfer to bipolar cells. Mol. Ther. 26, 1343–1353 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Cotman, S. L. et al. Cln3(Deltaex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth. Hum. Mol. Genet. 11, 2709–2721 (2002).

    CAS  PubMed  Google Scholar 

  158. Bosch, M. E. et al. Self-complementary AAV9 gene delivery partially corrects pathology associated with juvenile neuronal ceroid lipofuscinosis (CLN3). J. Neurosci. 36, 9669–9682 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Cain, J. T. et al. Testing safety and efficacy of AAV9-CLN6 gene therapy in a mouse model of CLN6-Batten disease [P11]. Presented at the 15th International Conference of Neuronal Ceroid Lipofuscinosis (Batten disease) in Boston, MA, USA (2016).

  160. Likhite, S. et al. Gene therapy for the CLN6 Batten disease: in vivo validation and safety study into a non-human primate model [P48]. Presented at the 15th International Conference of Neuronal Ceroid Lipofuscinosis (Batten disease) in Boston, MA, USA (2016).

  161. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02725580 (2018).

  162. Johnson T. B. et al. Intrathecal scAAV9-CLN3 administration: potential gene therapy for CLN3-Batten disease [abstract]. Presented at the 16th International Conference on Neuronal Ceroid Lipofuscinosis (2018).

  163. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/ct2/show/NCT03770572 (2018).

  164. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00151216 (2018).

  165. Worgall, S. 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. 19, 463–474 (2008).

    CAS  PubMed  Google Scholar 

  166. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01161576 (2018).

  167. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01414985 (2018).

  168. Wiley, L. A. et al. Using patient-specific induced pluripotent stem cells and wild-type mice to develop a gene augmentation-based strategy to treat CLN3-associated retinal degeneration. Hum. Gene Ther. 27, 835–846 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Wenzel, A., Grimm, C., Samardzija, M. & Reme, C. E. Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration. Prog. Retin. Eye Res. 24, 275–306 (2005).

    CAS  PubMed  Google Scholar 

  170. Wen, R., Tao, W., Li, Y. & Sieving, P. A. CNTF and retina. Prog. Retin. Eye Res. 31, 136–151 (2012).

    CAS  PubMed  Google Scholar 

  171. Jankowiak, W. et al. Sustained neural stem cell-based intraocular delivery of CNTF attenuates photoreceptor loss in the nclf mouse model of neuronal ceroid lipofuscinosis. PLOS ONE 10, e0127204 (2015).

    PubMed  PubMed Central  Google Scholar 

  172. Tracy, C. J. et al. Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis. Exp. Eye Res. 152, 77–87 (2016).

    CAS  PubMed  Google Scholar 

  173. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00337636 (2015).

  174. Arvan, P., Zhao, X., Ramos-Castaneda, J. & Chang, A. Secretory pathway quality control operating in Golgi, plasmalemmal, and endosomal systems. Traffic 3, 771–780 (2002).

    CAS  PubMed  Google Scholar 

  175. Ellgaard, L. & Helenius, A. ER quality control: towards an understanding at the molecular level. Curr. Opin. Cell Biol. 13, 431–437 (2001).

    CAS  PubMed  Google Scholar 

  176. Parenti, G. Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics. EMBO Mol. Med. 1, 268–279 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Valenzano, K. J. et al. Identification and characterization of pharmacological chaperones to correct enzyme deficiencies in lysosomal storage disorders. Assay Drug Dev. Technol. 9, 213–235 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Fan, J. Q. A counterintuitive approach to treat enzyme deficiencies: use of enzyme inhibitors for restoring mutant enzyme activity. Biol. Chem. 389, 1–11 (2008).

    CAS  PubMed  Google Scholar 

  179. Dawson, G., Schroeder, C. & Dawson, P. E. Palmitoyl:protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease. Biochem. Biophys. Res. Commun. 395, 66–69 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Kousi, M., Lehesjoki, A. E. & Mole, S. E. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum. Mutat. 33, 42–63 (2012).

    CAS  PubMed  Google Scholar 

  181. Roy, B. et al. Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression. Proc. Natl Acad. Sci. USA 113, 12508–12513 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Sleat, D. E., Sohar, I., Gin, R. M. & Lobel, P. Aminoglycoside-mediated suppression of nonsense mutations in late infantile neuronal ceroid lipofuscinosis. Eur. J. Paediatr. Neurol. 5 (Suppl. A), 57–62 (2001).

    PubMed  Google Scholar 

  183. Miller, J. N., Chan, C. H. & Pearce, D. A. The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis. Hum. Mol. Genet. 22, 2723–2734 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Schoch, K. M. & Miller, T. M. Antisense oligonucleotides: translation from mouse models to human neurodegenerative diseases. Neuron 94, 1056–1070 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Ramesh, N. & Pandey, U. B. Autophagy Dysregulation in ALS: when protein aggregates get out of hand. Front. Mol. Neurosci. 10, 263 (2017).

    PubMed  PubMed Central  Google Scholar 

  186. Uddin, M. S. et al. Autophagy and Alzheimer’s disease: from molecular mechanisms to therapeutic implications. Front. Aging Neurosci. 10, 04 (2018).

    PubMed  PubMed Central  Google Scholar 

  187. Wang, B., Abraham, N., Gao, G. & Yang, Q. Dysregulation of autophagy and mitochondrial function in Parkinson’s disease. Transl Neurodegener. 5, 19 (2016).

    PubMed  PubMed Central  Google Scholar 

  188. Koike, M. et al. Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am. J. Pathol. 167, 1713–1728 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Cao, Y. et al. Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. J. Biol. Chem. 281, 20483–20493 (2006).

    CAS  PubMed  Google Scholar 

  190. Cotman, S. L. & Staropoli, J. F. The juvenile Batten disease protein, CLN3, and its role in regulating anterograde and retrograde post-Golgi trafficking. Clin. Lipidol. 7, 79–91 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Behrends, C., Sowa, M. E., Gygi, S. P. & Harper, J. W. Network organization of the human autophagy system. Nature 466, 68–76 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Hong, M. et al. Fibrates inhibit the apoptosis of Batten disease lymphoblast cells via autophagy recovery and regulation of mitochondrial membrane potential. In Vitro Cell. Dev. Biol. Anim. 52, 349–355 (2016).

    CAS  PubMed  Google Scholar 

  193. Combs, C. K., Bates, P., Karlo, J. C. & Landreth, G. E. Regulation of beta-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor alpha. Neurochem. Int. 39, 449–457 (2001).

    CAS  PubMed  Google Scholar 

  194. Deplanque, D. et al. Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment. J. Neurosci. 23, 6264–6271 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Ghosh, A., Rangasamy, S. B., Modi, K. K. & Pahan, K. Gemfibrozil, food and drug administration-approved lipid-lowering drug, increases longevity in mouse model of late infantile neuronal ceroid lipofuscinosis. J. Neurochem. 141, 423–435 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Ghosh, A. et al. Activation of peroxisome proliferator-activated receptor alpha induces lysosomal biogenesis in brain cells: implications for lysosomal storage disorders. J. Biol. Chem. 290, 10309–10324 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).

    CAS  PubMed  Google Scholar 

  198. Palmieri, M. et al. mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases. Nat. Commun. 8, 14338 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Heras-Sandoval, D., Perez-Rojas, J. M., Hernandez-Damian, J. & Pedraza-Chaverri, J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal. 26, 2694–2701 (2014).

    CAS  PubMed  Google Scholar 

  200. Gavin, M. et al. Substrate reduction therapy in four patients with milder CLN1 mutations and juvenile-onset Batten disease using cysteamine bitartrate. JIMD Rep. 11, 87–92 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00028262 (2016).

  202. Groh, J. et al. Immune cells perturb axons and impair neuronal survival in a mouse model of infantile neuronal ceroid lipofuscinosis. Brain 136, 1083–1101 (2013).

    PubMed  Google Scholar 

  203. Groh, J. et al. Sialoadhesin promotes neuroinflammation-related disease progression in two mouse models of CLN disease. Glia 64, 792–809 (2016).

    PubMed  Google Scholar 

  204. Ramirez-Montealegre, D. et al. Autoimmunity to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Neurology 64, 743–745 (2005).

    CAS  PubMed  Google Scholar 

  205. Castaneda, J. A. & Pearce, D. A. Identification of alpha-fetoprotein as an autoantigen in juvenile Batten disease. Neurobiol. Dis. 29, 92–102 (2008).

    CAS  PubMed  Google Scholar 

  206. De Virgilio, A. et al. Parkinson’s disease: autoimmunity and neuroinflammation. Autoimmun. Rev. 15, 1005–1011 (2016).

    PubMed  Google Scholar 

  207. Khalid, S. I., Ampie, L., Kelly, R., Ladha, S. S. & Dardis, C. Immune modulation in the treatment of amyotrophic lateral sclerosis: a review of clinical trials. Front. Neurol. 8, 486 (2017).

    PubMed  PubMed Central  Google Scholar 

  208. McGeer, P. L., Rogers, J., McGeer & Inflammation, E. G. Antiinflammatory agents, and Alzheimer’s disease: the last 22 years. J. Alzheimers Dis. 54, 853–857 (2016).

    PubMed  Google Scholar 

  209. Spangenberg, E. E. & Green, K. N. Inflammation in Alzheimer’s disease: lessons learned from microglia-depletion models. Brain Behav. Immun. 61, 1–11 (2017).

    CAS  PubMed  Google Scholar 

  210. Dagher, N. N. et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J. Neuroinflamm. 12, 139 (2015).

    Google Scholar 

  211. Seehafer, S. S. et al. Immunosuppression alters disease severity in juvenile Batten disease mice. J. Neuroimmunol. 230, 169–172 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01399047 (2017).

  213. Brinkmann, V. et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 9, 883–897 (2010).

    CAS  PubMed  Google Scholar 

  214. Chun, J. & Brinkmann, V. A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov. Med. 12, 213–228 (2011).

    PubMed  PubMed Central  Google Scholar 

  215. Melzer, N. & Meuth, S. G. Disease-modifying therapy in multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy: common and divergent current and future strategies. Clin. Exp. Immunol. 175, 359–372 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Groh, J., Berve, K. & Martini, R. Fingolimod and teriflunomide attenuate neurodegeneration in mouse models of neuronal ceroid lipofuscinosis. Mol. Ther. 25, 1889–1899 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Aberg, L. et al. Intermittent prednisolone and autoantibodies to GAD65 in juvenile neuronal ceroid lipofuscinosis. Neurology 70, 1218–1220 (2008).

    CAS  PubMed  Google Scholar 

  218. Ahmad, I. et al. Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice. J. Neurosci. Res. 82, 811–821 (2005).

    CAS  PubMed  Google Scholar 

  219. Mellon, S. H., Gong, W. & Schonemann, M. D. Endogenous and synthetic neurosteroids in treatment of Niemann-Pick Type C disease. Brain Res. Rev. 57, 410–420 (2008).

    CAS  PubMed  Google Scholar 

  220. Reeves, E. K. M., Hoffman, E. P., Nagaraju, K., Damsker, J. M. & McCall, J. M. VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid. Bioorg. Med. Chem. 21, 2241–2249 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Aldrich, A. et al. Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3). Ann. Neurol. 80, 909–923 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Amor, S. et al. Inflammation in neurodegenerative diseases—an update. Immunology 142, 151–166 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Osuna-Zazuetal, M. A., Ponce-Gomez, J. A. & Perez-Neri, I. Neuroprotective mechanisms of cannabinoids in brain ischemia and neurodegenerative disorders [Spanish]. Invest. Clin. 56, 188–200 (2015).

    PubMed  Google Scholar 

  224. Nguyen, L. et al. Role of sigma-1 receptors in neurodegenerative diseases. J. Pharmacol. Sci. 127, 17–29 (2015).

    CAS  PubMed  Google Scholar 

  225. Dong, X. X., Wang, Y. & Qin, Z. H. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol. Sin. 30, 379–387 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Benitez-King, G., Ramirez-Rodriguez, G., Ortiz, L. & Meza, I. The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. Curr. Drug Targets CNS Neurol. Disord. 3, 515–533 (2004).

    CAS  PubMed  Google Scholar 

  227. Kim, G. H., Kim, J. E., Rhie, S. J. & Yoon, S. The role of oxidative stress in neurodegenerative diseases. Exp. Neurobiol. 24, 325–340 (2015).

    PubMed  PubMed Central  Google Scholar 

  228. Karuppagounder, S. S. et al. The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease. Sci. Rep. 4, 4874 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Zhang, S., Tang, M. B., Luo, H. Y., Shi, C. H. & Xu, Y. M. Necroptosis in neurodegenerative diseases: a potential therapeutic target. Cell Death Dis. 8, e2905 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Kovacs, A. D. et al. Temporary inhibition of AMPA receptors induces a prolonged improvement of motor performance in a mouse model of juvenile Batten disease. Neuropharmacology 60, 405–409 (2010).

    PubMed  PubMed Central  Google Scholar 

  231. Kovacs, A. D. & Pearce, D. A. Attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile Batten disease. Exp. Neurol. 209, 288–291 (2008).

    CAS  PubMed  Google Scholar 

  232. Sarkar, C. et al. Neuroprotection and lifespan extension in Ppt1(−/−) mice by NtBuHA: therapeutic implications for INCL. Nat. Neurosci. 16, 1608–1617 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Dhar, S. et al. Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons. Ann. Neurol. 51, 448–466 (2002).

    CAS  PubMed  Google Scholar 

  234. Cooper, J. et al. Testing combinatorial therapies for juvenile Batten disease. Mol. Genet. Metab. 123, S33 (2018).

    Google Scholar 

  235. Macauley, S. L. 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. 71, 797–804 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Agrawal, N. et al. Identification of combinatorial drug regimens for treatment of Huntington’s disease using Drosophila. Proc. Natl Acad. Sci. USA 102, 3777–3781 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Augustine, E. F., Adams, H. R. & Mink, J. W. Clinical trials in rare disease: challenges and opportunities. J. Child Neurol. 28, 1142–1150 (2013).

    PubMed  PubMed Central  Google Scholar 

  238. Timm, D. et al. Searching for novel biomarkers using a mouse model of CLN3-Batten disease. PLOS ONE 13, e0201470 (2018).

    PubMed  PubMed Central  Google Scholar 

  239. Hersrud, S. L., Geraets, R. D., Weber, K. L., Chan, C. H. & Pearce, D. A. Plasma biomarkers for neuronal ceroid lipofuscinosis. FEBS J. 283, 459–471 (2016).

    CAS  PubMed  Google Scholar 

  240. Stoller, J. K. The challenge of rare diseases. Chest 153, 1309–1314 (2018).

    PubMed  Google Scholar 

  241. US Department of Health & Human Services. Developing products for rare diseases & conditions. FDA.gov https://www.fda.gov/ForIndustry/ucm2005525.htm (updated 10 May 2018).

  242. Cialone, J. et al. Quantitative telemedicine ratings in Batten disease: implications for rare disease research. Neurology 77, 1808–1811 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Marshall, F. J. et al. A clinical rating scale for Batten disease: reliable and relevant for clinical trials. Neurology 65, 275–279 (2005).

    CAS  PubMed  Google Scholar 

  244. Schulz, A. et al. The DEM-CHILD NCL patient database: a tool for the evaluation of therapies in neuronal ceroid lipofuscinoses (NCL). Eur. J. Paediatr. Neurol. 19, S16 (2015).

    Google Scholar 

  245. Sanford Research. Welcome to the Coordination of Rare Diseases at Sanford (CoRDS)! Sanford Research http://www.sanfordresearch.org/SpecialPrograms/cords/ (2018).

  246. Vanhanen, S. L. et al. Neuroradiological findings (MRS, MRI, SPECT) in infantile neuronal ceroid-lipofuscinosis (infantile CLN1) at different stages of the disease. Neuropediatrics 35, 27–35 (2004).

    PubMed  Google Scholar 

  247. Vanhanen, S. L., Raininko, R., Autti, T. & Santavuori, P. MRI evaluation of the brain in infantile neuronal ceroid-lipofuscinosis. Part 2: MRI findings in 21 patients. J. Child Neurol. 10, 444–450 (1995).

    CAS  PubMed  Google Scholar 

  248. Vanhanen, S. L., Raininko, R. & Santavuori, P. Early differential diagnosis of infantile neuronal ceroid lipofuscinosis, Rett syndrome, and Krabbe disease by CT and MR. AJNR Am. J. Neuroradiol. 15, 1443–1453 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Vanhanen, S. L., Raininko, R., Santavuori, P., Autti, T. & Haltia, M. MRI evaluation of the brain in infantile neuronal ceroid-lipofuscinosis. Part 1: postmortem MRI with histopathologic correlation. J. Child Neurol. 10, 438–443 (1995).

    CAS  PubMed  Google Scholar 

  250. Vanhanen, S. L., Sainio, K., Lappi, M. & Santavuori, P. EEG and evoked potentials in infantile neuronal ceroid-lipofuscinosis. Dev. Med. Child Neurol. 39, 456–463 (1997).

    CAS  PubMed  Google Scholar 

  251. Veneselli, E., Biancheri, R., Buoni, S. & Fois, A. Clinical and EEG findings in 18 cases of late infantile neuronal ceroid lipofuscinosis. Brain Dev. 23, 306–311 (2001).

    CAS  PubMed  Google Scholar 

  252. Westmoreland, B. F., Groover, R. V. & Sharbrough, F. W. Electrographic findings in three types of cerebromacular degeneration. Mayo Clin. Proc. 54, 12–21 (1979).

    CAS  PubMed  Google Scholar 

  253. Kohlschutter, A., Gardiner, R. M. & Goebel, H. H. Human forms of neuronal ceroid-lipofuscinosis (Batten disease): consensus on diagnostic criteria, Hamburg 1992. J. Inherit. Metab. Dis. 16, 241–244 (1993).

    CAS  PubMed  Google Scholar 

  254. Baker, E. H., Levin, S. W., Zhang, Z. & Mukherjee, A. B. MRI brain volume measurements in infantile neuronal ceroid lipofuscinosis. AJNR Am. J. Neuroradiol. 38, 376–382 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  255. Santavuori, P., Raininko, R., Vanhanen, S. L., Launes, J. & Sainio, K. MRI of the brain, EEG sleep spindles and SPECT in the early diagnosis of infantile neuronal ceroid lipofuscinosis. Dev. Med. Child Neurol. 34, 61–65 (1992).

    CAS  PubMed  Google Scholar 

  256. Seitz, D. et al. MR imaging and localized proton MR spectroscopy in late infantile neuronal ceroid lipofuscinosis. AJNR Am. J. Neuroradiol. 19, 1373–1377 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Dyke, J. P. et al. Assessment of disease severity in late infantile neuronal ceroid lipofuscinosis using multiparametric MR imaging. AJNR Am. J. Neuroradiol. 34, 884–889 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Dyke, J. P. et al. Assessing disease severity in late infantile neuronal ceroid lipofuscinosis using quantitative MR diffusion-weighted imaging. AJNR Am. J. Neuroradiol. 28, 1232–1236 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Williams, R. E. et al. Management strategies for CLN2 disease. Pediatr. Neurol. 69, 102–112 (2017).

    PubMed  Google Scholar 

  260. Autti, T., Raininko, R., Launes, J., Nuutila, A. & Santavuori, P. Jansky-Bielschowsky variant disease: CT, MRI, and SPECT findings. Pediatr. Neurol. 8, 121–126 (1992).

    CAS  PubMed  Google Scholar 

  261. Autti, T., Raininko, R., Vanhanen, S. L. & Santavuori, P. Magnetic resonance techniques in neuronal ceroid lipofuscinoses and some other lysosomal diseases affecting the brain. Curr. Opin. Neurol. 10, 519–524 (1997).

    CAS  PubMed  Google Scholar 

  262. Jarvela, I. et al. Clinical and magnetic resonance imaging findings in Batten disease: analysis of the major mutation (1.02-kb deletion). Ann. Neurol. 42, 799–802 (1997).

    CAS  PubMed  Google Scholar 

  263. Eksandh, L. B. et al. Full-field ERG in patients with Batten/Spielmeyer-Vogt disease caused by mutations in the CLN3 gene. Ophthalmic Genet. 21, 69–77 (2000).

    CAS  PubMed  Google Scholar 

  264. Santavuori, P., Vanhanen, S. L. & Autti, T. Clinical and neuroradiological diagnostic aspects of neuronal ceroid lipofuscinoses disorders. Eur. J. Paediatr. Neurol. 5 (Suppl. A), 157–161 (2001).

    PubMed  Google Scholar 

  265. Cialone, J. et al. Females experience a more severe disease course in Batten disease. J. Inherit. Metab. Dis. 35, 549–555 (2012).

    PubMed  Google Scholar 

  266. Boustany, R. M., Alroy, J. & Kolodny, E. H. Clinical classification of neuronal ceroid-lipofuscinosis subtypes. Am. J. Med. Genet. Suppl. 5, 47–58 (1988).

    CAS  PubMed  Google Scholar 

  267. Burneo, J. G. et al. Adult-onset neuronal ceroid lipofuscinosis (Kufs disease) with autosomal dominant inheritance in Alabama. Epilepsia 44, 841–846 (2003).

    PubMed  Google Scholar 

  268. Holmberg, V. et al. Phenotype-genotype correlation in eight patients with Finnish variant late infantile NCL (CLN5). Neurology 55, 579–581 (2000).

    CAS  PubMed  Google Scholar 

  269. Canafoglia, L. et al. Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations. Neurology 85, 316–324 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Beesley, C. et al. CLN8 disease caused by large genomic deletions. Mol. Genet. Genomic Med. 5, 85–91 (2017).

    CAS  Google Scholar 

  271. Allen, N. M. et al. Variant late-infantile neuronal ceroid lipofuscinosis due to a novel heterozygous CLN8 mutation and de novo 8p23.3 deletion. Clin. Genet. 81, 602–604 (2012).

    CAS  PubMed  Google Scholar 

  272. Reinhardt, K. et al. Novel CLN8 mutations confirm the clinical and ethnic diversity of late infantile neuronal ceroid lipofuscinosis. Clin. Genet. 77, 79–85 (2010).

    CAS  PubMed  Google Scholar 

  273. Doccini, S. et al. Early infantile neuronal ceroid lipofuscinosis (CLN10 disease) associated with a novel mutation in CTSD. J. Neurol. 263, 1029–1032 (2016).

    PubMed  Google Scholar 

  274. Varvagiannis, K. et al. Congenital neuronal ceroid lipofuscinosis with a novel CTSD gene mutation: a rare cause of neonatal-onset neurodegenerative disorder. Neuropediatrics 49, 150–153 (2018).

    CAS  PubMed  Google Scholar 

  275. Smith, K. R. et al. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am. J. Hum. Genet. 90, 1102–1107 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. Di Fabio, R. et al. Pseudo-dominant inheritance of a novel CTSF mutation associated with type B Kufs disease. Neurology 83, 1769–1770 (2014).

    PubMed  Google Scholar 

  277. Smith, K. R. et al. Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis. Hum. Mol. Genet. 22, 1417–1423 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. Gupta, P. et al. Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proc. Natl Acad. Sci. USA 98, 13566–13571 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  279. Tamaki, S. J. 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 5, 310–319 (2009).

    CAS  PubMed  Google Scholar 

  280. Griffey, M., Macauley, S. L., Ogilvie, J. M. & Sands, M. S. AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis. Mol. Ther. 12, 413–421 (2005).

    CAS  PubMed  Google Scholar 

  281. Wei, H. et al. Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: partial rescue by resveratrol. Hum. Mol. Genet. 20, 1111–1121 (2011).

    CAS  PubMed  Google Scholar 

  282. Roberts, M. S. et al. Combination small molecule PPT1 mimetic and CNS-directed gene therapy as a treatment for infantile neuronal ceroid lipofuscinosis. J. Inherit. Metab. Dis. 35, 847–857 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  283. Rozenberg, A. J., Lykken, E., Spratt, K., Miller, T. J. & Gray, S. J. Combination dosing of CLN1 gene therapy extends lifespan in a mouse model of infantile neuronal ceroid lipofuscinosis. Mol. Genet. Metab. 123, S124 (2018).

    Google Scholar 

  284. Bible, E., Gupta, P., Hofmann, S. L. & Cooper, J. D. Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null mutant mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol. Dis. 16, 346–359 (2004).

    CAS  PubMed  Google Scholar 

  285. Kielar, C. et al. Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol. Dis. 25, 150–162 (2007).

    CAS  PubMed  Google Scholar 

  286. Macauley, S. L. et al. Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse. Exp. Neurol. 217, 124–135 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  287. Meng, Y. et al. A basic ApoE-based peptide mediator to deliver proteins across the blood-brain barrier: long-term efficacy, toxicity, and mechanism. Mol. Ther. 25, 1531–1543 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  288. Miller, J. N., Kovács, A. D. & Pearce, D. A. The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Hum. Mol. Genet. 24, 185–196 (2015).

    CAS  PubMed  Google Scholar 

  289. Thada, V., Miller, J. N., Kovacs, A. D. & Pearce, D. A. 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. 20, 381–385 (2016).

    CAS  PubMed  Google Scholar 

  290. Xu, S. et al. Large-volume intrathecal enzyme delivery increases survival of a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol. Ther. 19, 1842–1848 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. Passini, M. A. et al. Intracranial delivery of CLN2 reduces brain pathology in a mouse model of classical late infantile neuronal ceroid lipofuscinosis. J. Neurosci. 26, 1334–1342 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  292. Lin, L. & Lobel, P. Production and characterization of recombinant human CLN2 protein for enzyme-replacement therapy in late infantile neuronal ceroid lipofuscinosis. Biochem. J. 357, 49–55 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  293. Geraets, R. D. et al. A tailored mouse model of CLN2 disease: a nonsense mutant for testing personalized therapies. PLOS ONE 12, e0176526 (2017).

    PubMed  PubMed Central  Google Scholar 

  294. Katz, M. L. et al. A mouse gene knockout model for juvenile ceroid-lipofuscinosis (Batten disease). J. Neurosci. Res. 57, 551–556 (1999).

    CAS  PubMed  Google Scholar 

  295. Pontikis, C. C. et al. Late onset neurodegeneration in the Cln3−/− mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation. Brain Res. 1023, 231–242 (2004).

    CAS  PubMed  Google Scholar 

  296. Pontikis, C. C., Cotman, S. L., MacDonald, M. E. & Cooper, J. D. Thalamocortical neuron loss and localized astrocytosis in the Cln3Deltaex7/8 knock-in mouse model of Batten disease. Neurobiol. Dis. 20, 823–836 (2005).

    CAS  PubMed  Google Scholar 

  297. Katz, M. L., Johnson, G. S., Tullis, G. E. & Lei, B. Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis. Neurobiol. Dis. 29, 242–253 (2008).

    CAS  PubMed  Google Scholar 

  298. Osorio, N. S. et al. Neurodevelopmental delay in the Cln3Deltaex7/8 mouse model for Batten disease. Genes Brain Behav. 8, 337–345 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  299. Weimer, J. M. et al. Cerebellar defects in a mouse model of juvenile neuronal ceroid lipofuscinosis. Brain Res. 1266, 93–107 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  300. Schultz, M. L. et al. Modulating membrane fluidity corrects Batten disease phenotypes in vitro and in vivo. Neurobiol. Dis. 115, 182–193 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  301. Mitchison, H. M., Lim, M. J. & Cooper, J. D. Selectivity and types of cell death in the neuronal ceroid lipofuscinoses. Brain Pathol. 14, 86–96 (2004).

    CAS  PubMed  Google Scholar 

  302. Weimer, J. M. et al. Visual deficits in a mouse model of Batten disease are the result of optic nerve degeneration and loss of dorsal lateral geniculate thalamic neurons. Neurobiol. Dis. 22, 284–293 (2006).

    PubMed  PubMed Central  Google Scholar 

  303. Weimer, J. M. et al. Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis. Brain Res. 1162, 98–112 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  304. Sappington, R. M., Pearce, D. A. & Calkins, D. J. Optic nerve degeneration in a murine model of juvenile ceroid lipofuscinosis. Invest. Ophthalmol. Vis. Sci. 44, 3725–3731 (2003).

    PubMed  Google Scholar 

  305. Kovacs, A. D. et al. Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease. Neuropharmacology 63, 769–775 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  306. Kleine Holthaus, S. M., Smith, A. J., Mole, S. E. & Ali, R. R. Gene therapy approaches to treat the neurodegeneration and visual failure in neuronal ceroid lipofuscinoses. Adv. Exp. Med. Biol. 1074, 91–99 (2018).

    PubMed  Google Scholar 

  307. Rosato, F. E. et al. Selective arterial stimulation of secretin in localization of gastrinomas. Surg. Gynecol. Obstet. 171, 196–200 (1990).

    CAS  PubMed  Google Scholar 

  308. Morgan, J. P. et al. A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease. PLOS ONE 8, e78694 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  309. Bronson, R. T., Lake, B. D., Cook, S., Taylor, S. & Davisson, M. T. Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten’s disease). Ann. Neurol. 33, 381–385 (1993).

    CAS  PubMed  Google Scholar 

  310. Chang, B. et al. Retinal degeneration in motor neuron degeneration: a mouse model of ceroid lipofuscinosis. Invest. Ophthalmol. Vis. Sci. 35, 1071–1076 (1994).

    CAS  PubMed  Google Scholar 

  311. Messer, A., Manley, K. & Plummer, J. A. An early-onset congenic strain of the motor neuron degeneration (mnd) mouse. Mol. Genet. Metab. 66, 393–397 (1999).

    CAS  PubMed  Google Scholar 

  312. Fujita, K. et al. Increase of glial fibrillary acidic protein fragments in the spinal cord of motor neuron degeneration mutant mouse. Brain Res. 785, 31–40 (1998).

    CAS  PubMed  Google Scholar 

  313. Kuronen, M. et al. Galactolipid deficiency in the early pathogenesis of neuronal ceroid lipofuscinosis model Cln8mnd: implications to delayed myelination and oligodendrocyte maturation. Neuropathol. Appl. Neurobiol. 38, 471–486 (2012).

    CAS  PubMed  Google Scholar 

  314. Bolivar, V. J., Scott Ganus, J. & Messer, A. The development of behavioral abnormalities in the motor neuron degeneration (mnd) mouse. Brain Res. 937, 74–82 (2002).

    CAS  PubMed  Google Scholar 

  315. Bertamini, M. et al. Mitochondrial oxidative metabolism in motor neuron degeneration (mnd) mouse central nervous system. Eur. J. Neurosci. 16, 2291–2296 (2002).

    CAS  PubMed  Google Scholar 

  316. Elger, B. et al. Optimized synthesis of AMPA receptor antagonist ZK 187638 and neurobehavioral activity in a mouse model of neuronal ceroid lipofuscinosis. ChemMedChem 1, 1142–1148 (2006).

    CAS  PubMed  Google Scholar 

  317. Katz, M. L., Rice, L. M. & Gao, C. L. Dietary carnitine supplements slow disease progression in a putative mouse model for hereditary ceroid-lipofuscinosis. J. Neurosci. Res. 50, 123–132 (1997).

    CAS  PubMed  Google Scholar 

  318. Zeman, R. J., Peng, H. & Etlinger, J. D. Clenbuterol retards loss of motor function in motor neuron degeneration mice. Exp. Neurol. 187, 460–467 (2004).

    CAS  PubMed  Google Scholar 

  319. Koch, S. et al. Morphologic and functional correlates of synaptic pathology in the cathepsin D knockout mouse model of congenital neuronal ceroid lipofuscinosis. J. Neuropathol. Exp. Neurol. 70, 1089–1096 (2011).

    CAS  PubMed  Google Scholar 

  320. Koike, M. et al. Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J. Neurosci. 20, 6898–6906 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  321. Partanen, S. 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. 67, 16–29 (2008).

    CAS  PubMed  Google Scholar 

  322. Shevtsova, Z. et al. CNS-expressed cathepsin D prevents lymphopenia in a murine model of congenital neuronal ceroid lipofuscinosis. Am. J. Pathol. 177, 271–279 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

T.B.J., J.T.C., K.A.W. and J.M.W. are supported in part by funding to J.M.W. from the Charlotte and Gwenyth Gray Foundation, the Haley’s Heroes Foundation, the Beat Batten Foundation and the Sebastian Velona Foundation and from NIH R01NS082283.

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Nature Reviews Neurology thanks J. Mink and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Batten disease mutation database: http://www.ucl.ac.uk/ncl

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Johnson, T.B., Cain, J.T., White, K.A. et al. Therapeutic landscape for Batten disease: current treatments and future prospects. Nat Rev Neurol 15, 161–178 (2019). https://doi.org/10.1038/s41582-019-0138-8

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