Journal of Applied Genetics

, Volume 59, Issue 2, pp 187–191 | Cite as

A pilot study of direct delivery of hydroxypropyl-beta-cyclodextrin to the lung by the nasal route in a mouse model of Niemann-Pick C1 disease: motor performance is unaltered and lung disease is worsened

  • Robert P. Erickson
  • Gail Deutsch
  • Ruturaj Patil
Human Genetics • Short Communication


We have tested the efficacy of hydroxypropyl-beta-cyclodextrin (HPBCD) delivered by the nasal route in the mouse model of juvenile Niemann-Pick C1 disease (NPC1), as pulmonary disease has not responded to systemic therapy with this drug. Since mice have no gag reflex, coating of the nasal cavity, with possible access to the brain, would be followed by delivery of HPBCD to the lung. While foamy macrophages, containing stored cholesterol, were found in the Npc1 nmf164 homozygous mice, a marked inflammatory response was found with inhaled HPBCD, both in mutant and wild-type animals. Slight inflammation also occasionally occurred with saline inhalation. There was no difference between the saline-treated, HPBCD-treated, and untreated Npc1 nmf164 homozygous mice for weight, balance beam performance, or coat hanger performance. Interestingly, there was a trend to longer survival in the HPBCD-treated Npc1 nmf164 homozygous mice, which, when combined with the survival times of the saline-treated survivals (each of which was not different), became significant.


Niemann-Pick C1 disease Hydroxypropyl-beta-cyclodextrin Nasal delivery Lung inflammation Neurodegeneration 



We thank Maria Teresa Fiorenza for discussions and comments on the manuscript and Christina Marie Brentley and Yazmin Gonzales-Almazon for assistance.

Author’s contributions

Robert P. Erickson designed and participated in the experiments and authored the manuscript. Gail Deutsch performed the histological examinations and corrected the manuscript. Rutaraj Patil performed experiments and data analysis.

Funding information

This work was supported in part by grant no. NIH NICHD R25HD080811 (F Ghishan/F Garcia/M Witte—multiple PIs).

Compliance with ethical standards

Conflict of interest

All authors declare no conflicts of interest.

Ethics approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

13353_2018_431_MOESM1_ESM.docx (53 kb)
ESM 1 (DOCX 53 kb)


  1. Camargo F, Erickson RP, Garver WS et al (2001) Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease. Life Sci 70:131–142CrossRefPubMedGoogle Scholar
  2. Canterini S, Dragotto J, Dardis A, Zampieri S, De Stefano ME, Mangia MF, Erickson RP, Fiorenza MT (2017) Shortened primary cilium length and dysregulated sonic hedgehog signaling in Niemann-Pick C1 disease. Hum Mol Genet 26:2277–2289CrossRefPubMedGoogle Scholar
  3. Chien YH, Shieh YD, Yang CY, Lee NC, Hwu WL (2013) Lung toxicitiy of hydroxypropyl-beta-dyclodextrin infusion. Mol Genet Metab 1009:232–232Google Scholar
  4. Davidson CD, Ali NF, Micsenyi MC, Stephney G, Renault S, Dobrenis K, Ory DS, Vanier MT, Walkley SU (2009) Chronic cyclodextrin treatment of murine Niemann–Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS One 4(9):e6951. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Deutsch G, Muralidhar A, Le L, Borbon IA, Erickson RP (2016) Extensive macrophage accumulation in young and old Niemann-Pick C1 model mice involves the alternative, M2, activation pathway and inhibition of macrophage apoptosis. Gene 578:242–250CrossRefPubMedGoogle Scholar
  6. Erickson RP (2013) Current controversies in Niemann-Pick C1 disease: steroids or gangliiosides; neurons or neurons and glia. J Appl Genet 54:215–224CrossRefPubMedGoogle Scholar
  7. Erickson RP, Fiorenza MT (2017) A hopeful therapy for Niemann-Pick C1 disease. Lancet:1–2Google Scholar
  8. Evrard B, Bertholet P, Gueders M, Flament M-P, Piel G, Delattre L, Gayot A, Leterme P, Foidart J-M, Cataldo D (2004) Cyclodextrins as a potential carrier in drug nebulization. J Control Release 96:403–410CrossRefPubMedGoogle Scholar
  9. Illum L (2004) Is nose-to-brain transport of drugs in man a reality? J Pharm Pharmacol 56:3–17CrossRefPubMedGoogle Scholar
  10. Itaya SK (1987) Anterograde transsynapatic transport of WGA-HRP in rat olfactory pathways. Brain Res 409:205–214CrossRefPubMedGoogle Scholar
  11. Le VNP, Leterme P, Gayot A, Flament MP (2006) Aerosolization potential of cyclodextrins—influence of the operating conditions. PDA J Pharm SciTech 60:314–322Google Scholar
  12. Liu B, Turley SD, Burns DK, Miller AM, Repa JJ, Dietschy JM (2009) Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the Npc1−/− mouse. Proc Natl Acad Sci U S A 106:2377–2382CrossRefPubMedPubMedCentralGoogle Scholar
  13. Liu B, Ramirez M, Miller AN, Repa JJ, Turley SD, Dietschy JM (2010) Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid. J Lipid Res 51:933–944CrossRefPubMedPubMedCentralGoogle Scholar
  14. Maue RA, Burgess RW, Wang B, Wooley CM, Seburn KA, Vanier MR, Rogers MA, Chang CC, Chang T-Y, Harris BT, Graber DJ, Penatti CAA, Porter DM, Szwergold BS, Henderson LP, Totenhagen JW, Trouard TP, Borbon IA, Erickson RP (2012) A novel mouse model of Niemann-Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations. Hum Mol Genet 21:730–750CrossRefPubMedGoogle Scholar
  15. Muralidhar A, Borbon IA, Esharif KM, Ke W, Manacheril R, Daines M, Erickson RP (2011) Pulmonary function and pathology in hydroxypropyl-beta-cyclodextin-treated and untreated Npc1 −/− mice. Mol Genet Metab 103:142–147CrossRefPubMedPubMedCentralGoogle Scholar
  16. Nusca S, Canterini S, Palladino G, Bruno F, Mangia F, Erickson RP, Fiorenza MT (2014) A marked paucity of granule cells in the developing cerebellum of the Npc1 −/− mouse is corrected by a single injection of hydroxypropyl-beta-cyclodextrin. Neurobiol Dis 70:117–126CrossRefPubMedPubMedCentralGoogle Scholar
  17. Saunders NR, Liddelow SA, Dziegielewska KM (2012) Barrier mechanisms in the developing brain. Front Pharmacol 3:46CrossRefPubMedPubMedCentralGoogle Scholar
  18. Scholfer O, Mmischo B, Puschel W, Harzer K, Vanier MT (1998) Early-lethal pulmonary Niemann-Pick type C disease belonging to a second, rare genetic complementation group. Eur J Pediatr 157:45–49CrossRefGoogle Scholar
  19. Shipley MT (1985) Transport of molecules from nose to brain: transneural anaterograde and retrograde labelling in the rat olfactory system by wheat germ agglutinin-horse radish peroxidase applied to the nasal epithelium. Brain Res Bull 15:129–142CrossRefPubMedGoogle Scholar
  20. Sundada H, Horikoshi T, Lukawiak K, Sakakibara M (2010) Increase in excitability of RPeD11 results in memory enhancement of juvenile and adult Lymnaea stagnalis by predator-induced stress. Neurobiol Learn Mem 94(2):269–277. CrossRefGoogle Scholar
  21. Suzuki T, Arumugam P, Sakagami T, Lachmann N, Chalk C, Sallese A, Abe S, Trapnell C, Carey B, Moritz T, Malik P, Lutzko C, Wood RE, Trapnell BC (2014) Pulmonary macrophage transplantation. Nature 514:450–454CrossRefPubMedPubMedCentralGoogle Scholar
  22. Zhang M, Strnatka D, Donohue C, Hallows JL, Vincent I, Erickson RP (2008) Astrocyte-only Npc1 reduces neuronal cholesterol and triples life span of Npc1−/− mice. J Neurosci Res 86:2848–2856CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Institute of Plant Genetics, Polish Academy of Sciences, Poznan 2018

Authors and Affiliations

  • Robert P. Erickson
    • 1
  • Gail Deutsch
    • 2
  • Ruturaj Patil
    • 1
  1. 1.Department of PediatricsUniversity of Arizona College of MedicineTucsonUSA
  2. 2.Department of Pathology, Seattle Children’s HospitalUniversity of Washington School of MedicineSeattleUSA

Personalised recommendations