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Review

Current advancements in therapy for Niemann-Pick disease: progress and pitfalls

ORCID Icon &
Pages 1229-1247 | Received 20 Feb 2023, Accepted 15 May 2023, Published online: 21 May 2023

References

  • Te Vruchte D, Lloyd-Evans E, Veldman RJ, et al. Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport. J Biol Chem. 2004 Jun 18;279(25):26167–26175. DOI:10.1074/jbc.M311591200
  • Lloyd-Evans E, Morgan AJ, He X, et al. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med. 2008 Nov;14(11):1247–1255.
  • Reunert J, Lotz-Havla AS, Polo G, et al. Niemann-pick type C-2 disease: identification by analysis of plasma cholestane-3β,5α,6β-triol and further insight into the clinical phenotype. JIMD Rep. 2015;23:17–26.
  • Vanier MT, Gissen P, Bauer P, et al. Diagnostic tests for Niemann-Pick disease type C (NP-C): a critical review. Mol Genet Metab. 2016;118(4):244–254. DOI:10.1016/j.ymgme.2016.06.004
  • Jiang X, Sidhu R, Mydock-McGrane L, et al. Development of a bile acid-based newborn screen for Niemann-Pick disease type C. Sci Transl Med. 2016 May 4;8(337):337ra63. DOI:10.1126/scitranslmed.aaf2326
  • Giese A-K, Mascher H, Grittner U, et al. A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease. Orphanet J Rare Diseases. 2015;10:78.
  • Garver WS, Francis GA, Jelinek D, et al. The National Niemann-Pick C1 disease database: report of clinical features and health problems. Am J Med Genet A. 2007 Jun 1;143A(11):1204–1211. DOI:10.1002/ajmg.a.31735
  • Geberhiwot T, Moro A, Dardis A, et al. Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet J Rare Dis. 2018 Apr 6;13(1):50. DOI:10.1186/s13023-018-0785-7
  • Vanier MT. Complex lipid trafficking in Niemann-Pick disease type C. J Inherit Metab Dis. 2015;38(1):187–199.
  • Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010 Jun 3;5:16.
  • Pineda M, Walterfang M, Patterson MC. Miglustat in Niemann-Pick disease type C patients: a review. Orphanet J Rare Dis. 2018 Aug 15;13(1):140.
  • Bremova-Ertl T, Abel L, Walterfang M, et al. A cross-sectional, prospective ocular motor study in 72 patients with Niemann-Pick disease type C. Eur J Neurol. 2021 Sep;28(9):3040–3050.
  • Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003 Oct;64(4):269–281.
  • Bremova T, Strupp M. Vertical supranuclear gaze palsy in a toddler with Niemann-Pick Type C. Pediatr Neurol. 2017 Jul;72:94.
  • Hammerschmidt TG, de Oliveira Schmitt Ribas G, Saraiva-Pereira ML, et al. Molecular and biochemical biomarkers for diagnosis and therapy monitorization of Niemann-Pick type C patients. Int J Dev Neurosci. 2018 May;66:18–23.
  • Zervas M, Somers KL, Thrall MA, et al. Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol. 2001 Aug 21;11(16):1283–1287. DOI:10.1016/S0960-9822(01)00396-7
  • Patterson MC, Vecchio D, Prady H, et al. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 2007 Sep;6(9):765–772.
  • Patterson MC, Mengel E, Vanier MT, et al. Treatment outcomes following continuous miglustat therapy in patients with Niemann-Pick disease Type C: a final report of the NPC Registry. Orphanet J Rare Dis. 2020 Apr 25;15(1):104. DOI:10.1186/s13023-020-01363-2
  • Bowman EA, Walterfang M, Abel L, et al. Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat. J Neurol. 2015 Sep;262(9):2106–2114.
  • Wraith JE, Vecchio D, Jacklin E, et al. Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab. 2010 Apr;99(4):351–357.
  • Heron B, Valayannopoulos V, Baruteau J, et al. Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C. Orphanet J Rare Dis. 2012 Jun 7;7:36. DOI:10.1186/1750-1172-7-36
  • Patterson MC, Garver WS, Giugliani R, et al. Long-term survival outcomes of patients with Niemann-Pick disease type C receiving miglustat treatment: a large retrospective observational study. J Inherit Metab Dis. 2020 Sep;43(5):1060–1069.
  • Karimzadeh P, Tonekaboni SH, Ashrafi MR, et al. Effects of miglustat on stabilization of neurological disorder in Niemann-Pick disease type C: Iranian pediatric case series. J Child Neurol. 2013 Dec;28(12):1599–1606.
  • Fecarotta S, Romano A, Della Casa R, et al. Long term follow-up to evaluate the efficacy of miglustat treatment in Italian patients with Niemann-Pick disease type C. Orphanet J Rare Dis. 2015 Feb 27;10:22. DOI:10.1186/s13023-015-0240-y
  • Patterson MC, Mengel E, Vanier MT, et al. Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study. Orphanet J Rare Dis. 2015 May 28;10:65. DOI:10.1186/s13023-015-0284-z
  • Pineda M, Perez-Poyato MS, O’Callaghan M, et al. Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick disease type C: a case series. Mol Genet Metab. 2010 Apr;99(4):358–366.
  • Pineda M, Wraith JE, Mengel E, et al. Miglustat in patients with Niemann-Pick disease type C (NP-C): a multicenter observational retrospective cohort study. Mol Genet Metab. 2009 Nov;98(3):243–249.
  • Abel LA, Walterfang M, Stainer MJ, et al. Longitudinal assessment of reflexive and volitional saccades in Niemann-Pick Type C disease during treatment with miglustat. Orphanet J Rare Dis. 2015 Dec 21;10:160. DOI:10.1186/s13023-015-0377-8
  • Patterson MC, Vecchio D, Jacklin E, et al. Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol. 2010 Mar;25(3):300–305.
  • Fecarotta S, Amitrano M, Romano A, et al. The videofluoroscopic swallowing study shows a sustained improvement of dysphagia in children with Niemann-Pick disease type C after therapy with miglustat. Am J Med Genet A. 2011 Mar;155A(3):540–547.
  • Solomon BI, Munoz AM, Sinaii N, et al. Phenotypic expression of swallowing function in Niemann-Pick disease type C1. Orphanet J Rare Dis. 2022 Sep 5;17(1):342. DOI:10.1186/s13023-022-02472-w
  • Solomon BI, Smith AC, Sinaii N, et al. Association of Miglustat with Swallowing Outcomes in Niemann-Pick Disease, Type C1. JAMA Neurol. 2020 Dec 1;77(12):1564–1568. DOI:10.1001/jamaneurol.2020.3241
  • Agrawal N, Farhat NY, Sinaii N, et al. Neurofilament light chain in cerebrospinal fluid as a novel biomarker in evaluating both clinical severity and therapeutic response in Niemann-Pick disease, type C1. Genet Med. 2022 Dec 2;25(3):100349. DOI:10.1016/j.gim.2022.11.017
  • Bowman EA, Velakoulis D, Desmond P, et al. Longitudinal changes in white matter fractional anisotropy in adult-onset Niemann-Pick disease type C patients treated with miglustat. JIMD Rep. 2018;39:39–43.
  • Walterfang M, Di Biase MA, Cropley VL, et al. Imaging of neuroinflammation in adult Niemann-Pick type C disease: a cross-sectional study. Neurology. 2020 Apr 21;94(16):e1716–1725. DOI:10.1212/WNL.0000000000009287
  • Galanaud D, Tourbah A, Lehericy S, et al. 24 month-treatment with miglustat of three patients with Niemann-Pick disease type C: follow up using brain spectroscopy. Mol Genet Metab. 2009 Feb;96(2):55–58.
  • Gropman AL, Anderson A. Novel imaging technologies for genetic diagnoses in the inborn errors of metabolism. J Transl Genet Genom. 2020;4:429–445.
  • Lau MW, Lee RW, Miyamoto R, et al. Role of diffusion tensor imaging in prognostication and treatment monitoring in Niemann-Pick disease type C1. Diseases. 2016 Sep 8;4(4):29. DOI:10.3390/diseases4030029
  • Lau TY, Kao YH, Toh HB, et al. Brain hypometabolic changes in 14 adolescent-adult patients with Niemann-Pick disease type C assessed by 18F-fluorodeoxyglucose positron emission tomography. J Neurol. 2021 Oct;268(10):3878–3885.
  • Huang JY, Peng SF, Yang CC, et al. Neuroimaging findings in a brain with Niemann-Pick type C disease. J Formos Med Assoc. 2011 Aug;110(8):537–542.
  • Sedel F, Chabrol B, Audoin B, et al. Normalisation of brain spectroscopy findings in Niemann-Pick disease type C patients treated with miglustat. J Neurol. 2016 May;263(5):927–936.
  • Fu R, Wassif CA, Yanjanin NM, et al. Efficacy of N-acetylcysteine in phenotypic suppression of mouse models of Niemann-Pick disease, type C1. Hum Mol Genet. 2013;22(17):3508–3523. DOI:10.1093/hmg/ddt206
  • Hammerschmidt TG, Donida B, Raabe M, et al. Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the in vitro effect of combined therapy with antioxidants and β-cyclodextrin nanoparticles. Metab Brain Dis. 2022 Nov 30;38(2):507–518. DOI:10.1007/s11011-022-01128-9
  • Kaya E, Smith DA, Smith C, et al. Acetyl-leucine slows disease progression in lysosomal storage disorders. Brain Commun. 2021;3(1):fcaa148. DOI:10.1093/braincomms/fcaa148
  • Churchill GC, Strupp M, Factor C, et al. Acetylation turns leucine into a drug by membrane transporter switching. Sci Rep. 2021 Aug 4;11(1):15812. DOI:10.1038/s41598-021-95255-5
  • Churchill GC, Strupp M, Galione A, et al. Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance. PLoS ONE. 2020;15(2):e0229585. DOI:10.1371/journal.pone.0229585
  • Bremova T, Malinova V, Amraoui Y, et al. Acetyl-dl-leucine in Niemann-Pick type C: a case series. Neurology. 2015 Oct 20;85(16):1368–1375. DOI:10.1212/WNL.0000000000002041
  • Cortina-Borja M, Te Vruchte D, Mengel E, et al. Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease type C and for recruitment to clinical trials. Orphanet J Rare Dis. 2018 Aug 16;13(1):143. DOI:10.1186/s13023-018-0880-9
  • Bremova-Ertl T, Claassen J, Foltan T, et al. Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C. J Neurol. 2022 Mar;269(3):1651–1662.
  • Kennedy BE, LeBlanc VG, Mailman TM, et al. Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick Type C1-deficient murine brain. PLoS ONE. 2013;8(12):e82685. DOI:10.1371/journal.pone.0082685
  • Li D, Shao R, Wang N, et al. Sulforaphane activates a lysosome-dependent transcriptional program to mitigate oxidative stress. Autophagy. 2021 Apr;17(4):872–887.
  • Hammerschmidt TG, Guerreiro GB, Donida B, et al. Beneficial in vitro effect of N-acetylcysteine and coenzyme Q10 on DNA damage in neurodegenerative Niemann-Pick type C 1 disease: preliminary results. Naunyn Schmiedebergs Arch Pharmacol. 2023 Feb 16. DOI:10.1007/s00210-023-02423-7
  • Kirkegaard T, Roth AG, Petersen NH, et al. Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology. Nature. 2010 Jan 28;463(7280):549–553. DOI:10.1038/nature08710
  • Kirkegaard T, Gray J, Priestman DA, et al. Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Sci Transl Med. 2016 Sep 7;8(355):355ra118. DOI:10.1126/scitranslmed.aad9823
  • Petersen NHT, Klein P, Valacca C, et al. Arimoclomol increases the transcription of lysosomal genes, including NPC1 and NPC2, to facilitate lysosomal function. 18th Annual WORLDSymposium February 7-11, p. 20222021.
  • Mengel E, Bembi B, Del Toro M, et al. Clinical disease progression and biomarkers in Niemann-Pick disease type C: a prospective cohort study. Orphanet J Rare Dis. 2020 Nov 23;15(1):328. DOI:10.1186/s13023-020-01616-0
  • Mengel E, Patterson MC, Da Riol RM, et al. Efficacy and safety of arimoclomol in Niemann-Pick disease type C: results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment. J Inherit Metab Dis. 2021 Nov;44(6):1463–1480.
  • Landskroner K. Characterization of AZ-3102, a novel brain-penetrant small molecule, in the Niemann-Pick disease type C mouse model. Mol Genet Metab. 2021;135(2021):S15–132.
  • Gascon-Bayarri J, Simon PC, Llop R, et al. Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment. Medicine (Baltimore). 2022 Dec 2;101(48):e31471. DOI:10.1097/MD.0000000000031471
  • Fahrni ML, Misran NFL, Abidin ZZ, et al. Clinical predictors of efavirenz-based regimen treatment durability: a two-year case-control study of antiretroviral-naive patients. J Infect Public Health. 2023 Jan;16(1):96–103.
  • Mascherpa A, Ishii N, Tayagui A, et al. Lysosomal Targeting of β-Cyclodextrin. Chem Eur J. 2022 Oct 20;29(4):e202203252. DOI:10.1002/chem.202203252
  • Wehrmann ZT, Hulett TW, Huegel KL, et al. Quantitative comparison of the efficacy of various compounds in lowering intracellular cholesterol levels in Niemann-Pick type C fibroblasts. PLoS ONE. 2012;7(10):e48561. DOI:10.1371/journal.pone.0048561
  • Davidson CD, Ali NF, Micsenyi MC, et al. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS ONE. 2009 Sep 11;4(9):e6951. DOI:10.1371/journal.pone.0006951
  • Davidson J, Molitor E, Moores S, et al. 2-Hydroxypropyl-beta-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease. Biochim Biophys Acta, Mol Cell Biol Lipids. 2019 Oct;1864(10):1545–1561.
  • Vite CH, Bagel JH, Swain GP, et al. Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease. Sci Transl Med. 2015 Feb 25;7(276):276ra26. DOI:10.1126/scitranslmed.3010101
  • Ishitsuka Y, Irie T, Matsuo M. Cyclodextrins applied to the treatment of lysosomal storage disorders. Adv Drug Deliv Rev. 2022 Dec;191:114617.
  • Aqul A, Liu B, Ramirez CM, et al. Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment. J Neurosci. 2011 Jun 22;31(25):9404–9413. DOI:10.1523/JNEUROSCI.1317-11.2011
  • Davidson CD, Fishman YI, Puskas I, et al. Efficacy and ototoxicity of different cyclodextrins in Niemann-Pick C disease. Ann Clin Transl Neurol. 2016 May;3(5):366–380.
  • Donida B, Raabe M, Tauffner B, et al. Nanoparticles containing beta-cyclodextrin potentially useful for the treatment of Niemann-Pick C. J Inherit Metab Dis. 2020 May;43(3):586–601.
  • Ory DS, Ottinger EA, Farhat NY, et al. Intrathecal 2-hydroxypropyl-beta-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial. Lancet. 2017 Oct 14;390(10104):1758–1768. DOI:10.1016/S0140-6736(17)31465-4
  • Berry-Kravis E, Chin J, Hoffmann A, et al. Long-Term treatment of Niemann-Pick type C1 disease with intrathecal 2-hydroxypropyl-beta-cyclodextrin. Pediatr Neurol. 2018 Mar;80:24–34.
  • Hastings C, Vieira C, Liu B, et al. Expanded access with intravenous hydroxypropyl-beta-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis. Orphanet J Rare Dis. 2019 Oct 21;14(1):228. DOI:10.1186/s13023-019-1207-1
  • Hastings C, Liu B, Hurst B, et al. Intravenous 2-hydroxypropyl-beta-cyclodextrin (Trappsol(r) Cyclo) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: results of a phase 1 trial. Mol Genet Metab. 2022 Dec;137(4):309–319.
  • Reynolds M, Linneman LA, Luna S, et al. A phase 1/2 open label nonrandomized clinical trial of intravenous 2-hydroxypropyl-beta-cyclodextrin for acute liver disease in infants with Niemann-Pick C1. Mol Genet Metab Rep. 2021 Sep;28:100772.
  • Newton J, Hait NC, Maceyka M, et al. FTY720/Fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts. Faseb J. 2017 Apr;31(4):1719–1730.
  • Hait NC, Wise LE, Allegood JC, et al. Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat Neurosci. 2014 Jul;17(7):971–980.
  • Hughes MP, Smith DA, Morris L, et al. AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease. Hum Mol Genet. 2018 Sep 1;27(17):3079–3098. DOI:10.1093/hmg/ddy212
  • Kurokawa Y, Osaka H, Kouga T, et al. Gene therapy in a mouse model of Niemann-Pick disease type C1. Hum Gene Ther. 2021 Jun;32(11–12):589–598.
  • Platt FM, Neises GR, Dwek RA, et al. N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. J Biol Chem. 1994;269(11):8362–8365. DOI:10.1016/S0021-9258(17)37202-2
  • Treiber A, Morand O, Clozel M. The pharmacokinetics and tissue distribution of the glucosylceramide synthase inhibitor miglustat in the rat. Xenobiotica. 2007;37(3):298–314.
  • Zervas M, Dobrenis K, Walkley SU. Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J Neuropathol Exp Neurol. 2001;60(1):49–64.
  • Stein VM, Crooks A, Ding W, et al. Miglustat improves purkinje cell survival and alters microglial phenotype in feline Niemann-Pick disease type C. J Neuropathol Exp Neurol. 2012;71(5):434–448. DOI:10.1097/NEN.0b013e31825414a6
  • Williams IM, Wallom K-L, Smith DA, et al. Improved neuroprotection using miglustat, curcumin and ibuprofen as a triple combination therapy in Niemann-Pick disease type C1 mice. Neurobiol Dis. 2014;67:9–17.
  • Wraith JE, Imrie J. New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat. Ther Clin Risk Manag. 2009;5:877–887.
  • Walterfang M, Macfarlane MD, Looi JCL, et al. Pontine-to-midbrain ratio indexes ocular-motor function and illness stage in adult Niemann-Pick disease type C. Eur J Neurol. 2012;19(3):462–467. DOI:10.1111/j.1468-1331.2011.03545.x
  • Subramanian K, Rauniyar N, Lavallee-Adam M, et al. Quantitative analysis of the proteome response to the Histone Deacetylase Inhibitor (HDACi) VOrinostat in Niemann-Pick Type C1 disease. Mol & Cell Proteomics. 2017 Nov;16(11):1938–1957.
  • Munkacsi AB, Hammond N, Schneider RT, et al. Normalization of hepatic homeostasis in the npc1(nmf164) mouse model of Niemann-Pick type C disease treated with the histone deacetylase inhibitor vorinostat. J Biol Chem. 2017 Mar 17;292(11):4395–4410. DOI:10.1074/jbc.M116.770578
  • Alam MS, Cooper B, Farris JD, et al. Tolerance of chronic HDACi treatment for neurological, visceral and lung Niemann-Pick Type C disease in mice. Sci Rep. 2018 Mar 1;8(1):3875. DOI:10.1038/s41598-018-22162-7
  • Vibert N, Vidal PP. In vitro effects of acetyl-DL-leucine (tanganil) on central vestibular neurons and vestibulo-ocular networks of the guinea-pig. Eur J Neurosci. 2001 Feb;13(4):735–748.
  • Bremova-Ertl T, Platt F, Strupp M. Sandhoff disease: improvement of gait by Acetyl-DL-Leucine: a case report. Neuropediatrics. 2020 Dec;51(6):450–452.
  • Sarkar C, Lipinski MM. N-acetyl-L-leucine: a promising treatment option for traumatic brain injury. Neural Regen Res. 2022 Sep;17(9):1957–1958.
  • Ananieva EA, Powell JD, Hutson SM. Leucine metabolism in T cell activation: mTOR signaling and beyond. Adv Nutr. 2016 Jul;7(4):798S–805S.
  • Yudkoff M, Daikhin Y, Nissim I, et al. Brain amino acid requirements and toxicity: the example of leucine. J Nutr. 2005 Jun;135(6 Suppl):1531S–1538S.
  • Fu R, Yanjanin NM, Bianconi S, et al. Oxidative stress in Niemann-Pick disease, type C. Mol Genet Metab. 2010;101(2–3):214–218. DOI:10.1016/j.ymgme.2010.06.018
  • Ulatowski L, Parker R, Davidson C, et al. Altered vitamin E status in Niemann-Pick type C disease. J Lipid Res. 2011;52(7):1400–1410. DOI:10.1194/jlr.M015560
  • Xu M, Liu K, Swaroop M, et al. Delta-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders. J Biol Chem. 2012 Nov 16;287(47):39349–39360. DOI:10.1074/jbc.M112.357707
  • Smith D, Wallom K-L, Williams IM, et al. Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann-Pick disease type C1. Neurobiol Dis. 2009;36(2):242–251. DOI:10.1016/j.nbd.2009.07.010
  • Park WD, O’Brien JF, Lundquist PA, et al. Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum Mutat. 2003 Oct;22(4):313–325.
  • Gray J, Fernandez-Suarez ME, Falah M, et al. Heat shock protein amplification improves cerebellar myelination in the Npc1(nih) mouse model. EBioMedicine. 2022 Dec;86:104374.
  • Yanjanin NM, Velez JI, Gropman A, et al. Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C. Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):132–140. DOI:10.1002/ajmg.b.30969
  • Berry-Kravis E. Niemann-Pick disease, type C: diagnosis, management and disease-targeted therapies in development. Semin Pediatr Neurol. 2021 Apr;37:100879.
  • Liu B. Therapeutic potential of cyclodextrins in the treatment of Niemann-Pick type C disease. Clin Lipidol. 2012 Jun;7(3):289–301.
  • Liu B, Li H, Repa JJ, et al. Genetic variations and treatments that affect the lifespan of the NPC1 mouse. J Lipid Res. 2008 Mar;49(3):663–669.
  • Ramirez CM, Liu B, Taylor AM, et al. Weekly cyclodextrin administration normalizes cholesterol metabolism in nearly every organ of the Niemann-Pick type C1 mouse and markedly prolongs life. Pediatr Res. 2010 Oct;68(4):309–315.
  • Brachet A, Norwood S, Brouwers JF, et al. LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery. J Cell Bio. 2015 Mar 16;208(6):791–806. DOI:10.1083/jcb.201407122
  • Sodero AO, Vriens J, Ghosh D, et al. Cholesterol loss during glutamate-mediated excitotoxicity. Embo J. 2012 Apr 4;31(7):1764–1773. DOI:10.1038/emboj.2012.31
  • Sodero AO, Weissmann C, Ledesma MD, et al. Cellular stress from excitatory neurotransmission contributes to cholesterol loss in hippocampal neurons aging in vitro. Neurobiol Aging. 2011 Jun;32(6):1043–1053.
  • Mitroi DN, Pereyra-Gomez G, Soto-Huelin B, et al. NPC1 enables cholesterol mobilization during long-term potentiation that can be restored in Niemann-Pick disease type C by CYP46A1 activation. EMBO Rep. 2019 Nov 5;20(11):e48143. DOI:10.15252/embr.201948143
  • Hobson AD, Harris CM, van der Kam EL, et al. Discovery of A-971432, an orally bioavailable selective sphingosine-1-phosphate receptor 5 (S1P5) agonist for the potential treatment of neurodegenerative disorders. J Med Chem. 2015 Dec 10;58(23):9154–9170. DOI:10.1021/acs.jmedchem.5b00928
  • Grosso Jasutkar H, Oh SE, Mouradian MM. Therapeutics in the pipeline targeting alpha-synuclein for parkinson’s disease. Pharmacol Rev. 2022 Jan;74(1):207–237.
  • van der Kam E, van Bergeijk J, Mueller R, et al. The use of selective sphingosine-1-phosphate receptor 5 agonists for the treatment of neurodegenerative disorders such as alzheimer’s disease and lysosomal storage diseases such as Niemann-Pick c disease. Alzheimer’s Dement. 2014. Abstract DT-01-05, Alzheimer’s Imaging Consortium (IC): IC-02: Preclinical Alzheimer’s Disease and Biomarkers.
  • Pipalia NH, Saad SZ, Subramanian K, et al. HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts. J Lipid Res. 2021;62:100114.
  • Pipalia NH, Subramanian K, Mao S, et al. Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells. J Lipid Res. 2017 Apr;58(4):695–708.
  • Cruz DL, Pipalia N, Mao S, et al. Inhibition of histone deacetylases 1, 2, and 3 enhances clearance of cholesterol accumulation in Niemann-Pick C1 fibroblasts. ACS Pharmacol Transl Sci. 2021 Jun 11;4(3):1136–1148. DOI:10.1021/acsptsci.1c00033
  • Rauniyar N, Subramanian K, Lavallee-Adam M, et al. Quantitative proteomics of human fibroblasts with I1061T Mutation in Niemann-Pick C1 (NPC1) protein provides insights into the disease pathogenesis. Mol & Cell Proteomics. 2015 Jul;14(7):1734–1749.
  • Alam MS, Getz M, Haldar K. Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model. Sci Transl Med. 2016 Feb 17;8(326):326ra23.
  • Phase 1/2 study of vorinostat therapy in Niemann-Pick disease, type C1. Available from: https://clinicaltrials.gov/ct2/show/NCT02124083
  • Monahan PE, Negrier C, Tarantino M, et al. Emerging immunogenicity and genotoxicity considerations of adeno-associated virus vector gene therapy for hemophilia. J Clin Med. 2021 Jun 2;10(11):2471. DOI:10.3390/jcm10112471
  • Ashikawa H, Mogi H, Honda T, et al. Beneficial effects of primidone in Niemann-Pick disease type C (NPC)-model cells and mice: reduction of unesterified cholesterol levels in cells and extension of lifespan in mice. Eur J Pharmacol. 2021 Apr 5;896:173907. DOI:10.1016/j.ejphar.2021.173907
  • Pepponi R, De Simone R, De Nuccio C, et al. Repurposing dipyridamole in Niemann-Pick type C disease: a proof of concept study. Int J Mol Sci. 2022 Mar 22;23(7):3456. DOI:10.3390/ijms23073456
  • Zhou SY, Xu SJ, Yan YG, et al. Decreased purinergic inhibition of synaptic activity in a mouse model of Niemann-Pick disease type C [Research Support, Non-U.S. Gov’t]. Hippocampus. 2011 Feb;21(2):212–219.
  • Ferrante A, Pezzola A, Matteucci A, et al. The adenosine A(2A) receptor agonist T1-11 ameliorates neurovisceral symptoms and extends the lifespan of a mouse model of Niemann-Pick type C disease. Neurobiol Dis. 2018 Feb;110:1–11.
  • Schultz ML, Fawaz MV, Azaria RD, et al. Synthetic high-density lipoprotein nanoparticles for the treatment of Niemann-Pick diseases. BMC Med. 2019 Nov 11;17(1):200. DOI:10.1186/s12916-019-1423-5
  • Van Hoecke L, Van Cauwenberghe C, Borger V, et al. Anti-inflammatory mesenchymal stromal cell-derived extracellular vesicles improve pathology in Niemann–Pick type C disease. Biomedicines. 2021 Dec 8;9(12):1864. DOI:10.3390/biomedicines9121864
  • Lee H, Lee JK, Min WK, et al. Bone marrow-derived mesenchymal stem cells prevent the loss of Niemann-Pick type C mouse Purkinje neurons by correcting sphingolipid metabolism and increasing sphingosine-1-phosphate. Stem Cells. 2010 Apr;28(4):821–831.
  • Lee H, Kang JE, Lee JK, et al. Bone-marrow-derived mesenchymal stem cells promote proliferation and neuronal differentiation of Niemann-Pick type C mouse neural stem cells by upregulation and secretion of CCL2. Hum Gene Ther. 2013 Jul;24(7):655–669.
  • Hong YR, Lee H, Park MH, et al. CCL2 induces neural stem cell proliferation and neuronal differentiation in Niemann-Pick type C mice. J Vet Med Sci. 2015 Jun;77(6):693–699.
  • Hong S, Lee SE, Kang I, et al. Induced neural stem cells from human patient-derived fibroblasts attenuate neurodegeneration in Niemann-Pick type C mice. J Vet Sci. 2021 Jan;22(1):e7.
  • Cougnoux A, Yerger JC, Fellmeth M, et al. Reduction of glutamate neurotoxicity: a novel therapeutic approach for Niemann-Pick disease, type C1. Mol Genet Metab. 2021 Dec;134(4):330–336.
  • Pugach EK, Feltes M, Kaufman RJ, et al. High-content screen for modifiers of Niemann-Pick type C disease in patient cells. Hum Mol Genet. 2018 Jun 15;27(12):2101–2112. DOI:10.1093/hmg/ddy117
  • Alvarez AR, Klein A, Castro J, et al. Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease. Faseb J. 2008 Oct;22(10):3617–3627.
  • Cougnoux A, Cluzeau C, Mitra S, et al. Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target. Cell Death Dis. 2016 Mar 17;7(3):e2147. DOI:10.1038/cddis.2016.16
  • Pluvinage JV, Sun J, Claes C, et al. The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C. Sci Transl Med. 2021 Dec;13(622):eabg2919.
  • Colombo A, Dinkel L, Muller SA, et al. Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia. Nat Commun. 2021 Feb 24;12(1):1158. DOI:10.1038/s41467-021-21428-5
  • Evans WRH, Nicoli ER, Wang RY, et al. Case Report: ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases. Wellcome Open Res. 2017;2:75.
  • Brown A, Patel S, Ward C, et al. PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder. Sci Rep. 2016 Aug 30;6:31750. DOI:10.1038/srep31750
  • Ubeda Tikkanen A, Buxton K, Ullrich CK, et al. The palliative use of intrathecal baclofen in Niemann-Pick disease type C. Pediatrics. 2019 Nov;144(5). DOI:10.1542/peds.2019-1438.
  • Holler A, Albrecht U, Baumgartner Sigl S, et al. Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C. Mol Genet Metab Rep. 2021 Jun;27:100723.
  • Fields T, Patterson M, Bremova-Ertl T, et al. A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. Trials. 2021 Jan 22;22(1):84. DOI:10.1186/s13063-020-05009-3

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