Combination small molecule PPT1 mimetic and CNS-directed gene therapy as a treatment for infantile neuronal ceroid lipofuscinosis

详细信息    查看全文

• 作者：Marie S. Roberts (1)
  Shannon L. Macauley (1)
  Andrew M. Wong (2)
  Denis Yilmas (2)
  Sarah Hohm (1)
  Jonathan D. Cooper (2)
  Mark S. Sands (1) msands@dom.wustl.edu
• 刊名：Journal of Inherited Metabolic Disease
• 出版年：2012
• 出版时间：September 2012
• 年：2012
• 卷：35
• 期：5
• 页码：847-857
• 全文大小：641.2 KB
• 参考文献：1. Bible E, Gupta P, Hofmann SL, Cooper JD (2004) Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null mutant mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 16:346R11;359
  2. Burger C, Gorbatyuk OS, Velardo MJ, Peden CS, Williams P, Zolotukhin S, Reier PJ, Mandel RJ, Muzyczka N (2004) Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol Ther 10:302R11;317
  3. Das AK, Becerra CH, Yi W, Lu JY, Siakotos AN, Wisniewski KE, Hofmann SL (1998) Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. J Clin Invest 102:361R11;370
  4. Davidson BL, Stein CS, Heth JA, Martins I, Kotin RM, Derksen, Zabner J, Ghodsi A, Chiorini JA (2000) Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc Natl Acad Sci 97:3428R11;3432
  5. Galvin N, Vogler C, Levy B, Kovacs A, Griffey M, Sands MS (2008) A murine model of infantile neuronal ceroid lipofuscinosisR12;ultrastructural evaluation of storage in the central nervous system and viscera. Pediatr Dev Pathol 11:185R11;192
  6. Griffey M, Bible E, Vogler C, Levy B, Gupta P, Cooper J, Sands MS (2004) 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 16:360R11;369
  7. Griffey M, Macauley SL, Ogilvie JM, Sands MS (2005) AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis. Mol Ther 12:413R11;421
  8. Griffey MA, Wozniak D, Wong M, Bible E, Johnson K, Rothman SM, Wentz AE et al (2006) CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis. Mol Ther 13:538R11;547
  9. Gupta P, Soyombo AA, Atashband A, Wisniewski KE, Shelton JM, Richardson JA, Hammer RE et al (2001) Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proc Natl Acad Sci USA 98:13566R11;13571
  10. Haltia M, Rapola J, Santavuori P (1973a) Infantile type of so-called neuronal ceroid-lipofuscinosis. Histological and electron microscopic studies. Acta Neuropathol (Berl) 26:157R11;170
  11. Haltia M, Rapola J, Santavuori P, Keranen A (1973b) Infantile type of so-called neuronal ceroid-lipofuscinosis. 2. Morphological and biochemical studies. J Neurol Sci 18:269R11;285
  12. Haltia M, Tyynela J, Baumann M, Henseler M, Sandhoff K (1995) Immunological studies on sphingolipid activator proteins in the neuronal ceroid-lipofuscinoses. Gerontology 41(Suppl 2):239R11;248
  13. Hofmann SL, Peltonen L (2001) The neuronal ceroid lipofuscinosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. New York, McGraw-Hill, pp 3877R11;3894
  14. Hofmann SL, Das AK, Yi W, Lu JY, Wisniewski KE (1999) Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency. Mol Genet Metab 66:234R11;239
  15. Hofman IL, van der Wal AC, Dingemans KP, Becker AE (2001) Cardiac pathology in neuronal ceroid lipofuscinosesR12;a clinicopathologic correlation in three patients. Eur J Paediatr Neurol 5(Suppl A):213R11;217
  16. Kielar C, Maddox L, Bible E, Pontikis CC, Macauley SL, Griffey MA, Wong M et al (2007) Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 25:150R11;162
  17. Kielar C, Wishart TM, Palmer A, Dihanich S, Wong AM, Macauley SL, Chan CH et al (2009) Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease. Hum Mol Genet 18:4066R11;4080
  18. Lu JY, Hofmann SL (2006) Inefficient cleavage of palmitoyl-protein thioesterase (PPT) substrates by aminothiols: implications for treatment of infantile neuronal ceroid lipofuscinosis. J Inherit Metab Dis 29:119R11;126
  19. Macauley SL, Wozniak DF, Kielar C, Tan Y, Cooper JD, Sands MS (2009) Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse. Exp Neurol 217:124R11;135
  20. Mitchison HM, Hofmann SL, Becerra CH, Munroe PB, Lake BD, Crow YJ, Stephenson JB et al (1998) Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. Hum Mol Genet 7:291R11;297
  21. Mitchison HM, Lim MJ, Cooper JD (2004) Selectivity and types of cell death in the neuronal ceroid lipofuscinoses. Brain Pathol 14:86R11;96
  22. Passini MA, Macauley SL, Huff MR, Taksir TV, Bu J, Wu IH, Piepenhagen PA et al (2005) AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease. Mol Ther 11:754R11;762
  23. Sands MS, Barker J, Vogler C, Levy B, Gwynn B, Galvin N, Birkenmeier EH (1993) Treatment of murine mucopolysaccharidosis type VII in newborns by syngeneic bone marrow transplantation. Lab. Invest. 68:676R11;686
  24. Tamaki SJ, Jacobs Y, Dohse M, Capela A, Cooper JD, Reitsma M, He D et al (2009) Neuroprotection of host cells by human central nervous system stem cells in a mouse model of infantile neuronal ceroid lipofuscinosis. Cell Stem Cell 5:310R11;319
  25. Vanhanen SL, Sainio K, Lappi M, Santavuori P (1997) EEG and evoked potentials in infantile neuronal ceroid-lipofuscinosis. Dev Med Child Neurol 39:456R11;463
  26. Vesa J, Hellsten E, Verkruyse LA, Camp LA, Rapola J, Santavuori P, Hofmann SL et al (1995) Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376:584R11;587
  27. Wei H, Zhang Z, Saha A, Peng S, Chandra G, Quezado Z, Mukherjee AB (2011) Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: partial rescue by resveratrol. Hum Mol Genet 20:1111R11;1121
  28. Zhang Z, Butler JD, Levin SW, Wisniewski KE, Brooks SS, Mukherjee AB (2001) Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med 7:478R11;484
• 作者单位：1. Department of Internal Medicine, Washington University School of Medicine, Campus Box 8007, 660 S. Euclid Ave., St. Louis, MO 63110, USA2. Pediatric Storage Disorders Laboratory, Department of Neuroscience and MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King鈥檚 College London, London, SE5 9NU UK
• ISSN：1573-2665

文摘

Infantile neuronal ceroid lipofuscinosis (INCL) is a profoundly neurodegenerative disease of children caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). There is currently no effective therapy for this invariably fatal disease. To date, preclinical experiments using single treatments have resulted in incremental clinical improvements. Therefore, we determined the efficacy of CNS-directed AAV2/5-mediated gene therapy alone and in combination with the systemic delivery of the lysosomotropic PPT1 mimetic phosphocysteamine. Since CNS-directed gene therapy provides relatively high levels of PPT1 activity to specific regions of the brain, we hypothesized that phosphocysteamine would complement that activity in regions expressing subtherapeutic levels of the enzyme. Results indicate that CNS-directed gene therapy alone provided the greatest improvements in biochemical and histological measures as well as motor function and life span. Phosphocysteamine alone resulted in only minor improvements in motor function and no increase in lifespan. Interestingly, phosphocysteamine did not increase the biochemical and histological response when combined with AAV2/5-mediated gene therapy, but it did result in an additional improvement in motor function. These data suggest that a CNS-directed gene therapy approach provides significant clinical benefit, and the addition of the small molecule PPT1 mimetic can further increase that response.