Suppression of choroid plexus transthyretin levels by antisense oligonucleotide treatment

Merrill Benson, Richard A. Smith, Gene Hung, Barbara Kluve-Beckerman, Aaron D. Showalter, Kyle W. Sloop, Brett P. Monia

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Leptomeningeal amyloidosis associated with mutations in transthyretin (TTR) is a rare but fatal form of amyloidosis. Dementia and intracerebral haemorrhage are prominent features of this disease for which no specific therapy is known. In previous studies, we have shown that antisense oligonucleotides (ASOs) specific for human TTR could inhibit hepatic synthesis of TTR in mice transgenic for a human amyloid-associated TTR and may offer a medical means of treating systemic TTR amyloidosis. Parenteral administration of TTR-specific ASO, however, had no effect on the expression of TTR by the choroid plexus, which is believed to be the source of the amyloid protein in patients who have leptomeningeal amyloidosis. In the present study, mice transgenic for the human TTR amyloid-associated mutation Ile84Ser were treated by administration of TTR-specific ASO (50μgor 75μgper day) via an osmotic pump into the cerebral ventricular system over a 4-week period. Intraventricular administration of TTR-specific ASO significantly reduced choroid human TTR mRNA levels, and these findings correlated with decreased TTR in choroid plexus epithelial cells as demonstrated by immunohistochemistry. Suppression of choroid TTR expression by intraventricular administered ASO may offer a medical means of treating leptomeningeal amyloidosis.

Original languageEnglish
Pages (from-to)43-49
Number of pages7
JournalAmyloid
Volume17
Issue number2
DOIs
StatePublished - Jun 2010

Fingerprint

Choroid Plexus
Prealbumin
Antisense Oligonucleotides
Amyloidosis
Therapeutics
Choroid
Amyloid
Transgenic Mice
Amyloidogenic Proteins
Cerebral Ventricles
Mutation
Cerebral Hemorrhage
Dementia
Epithelial Cells
Immunohistochemistry

Keywords

  • Amyloidosis
  • Choroid plexus
  • Dementia
  • Hydrocephalus
  • Intracerebral haemorrhage
  • Transthyretin

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Benson, M., Smith, R. A., Hung, G., Kluve-Beckerman, B., Showalter, A. D., Sloop, K. W., & Monia, B. P. (2010). Suppression of choroid plexus transthyretin levels by antisense oligonucleotide treatment. Amyloid, 17(2), 43-49. https://doi.org/10.3109/13506129.2010.483121

Suppression of choroid plexus transthyretin levels by antisense oligonucleotide treatment. / Benson, Merrill; Smith, Richard A.; Hung, Gene; Kluve-Beckerman, Barbara; Showalter, Aaron D.; Sloop, Kyle W.; Monia, Brett P.

In: Amyloid, Vol. 17, No. 2, 06.2010, p. 43-49.

Research output: Contribution to journalArticle

Benson, M, Smith, RA, Hung, G, Kluve-Beckerman, B, Showalter, AD, Sloop, KW & Monia, BP 2010, 'Suppression of choroid plexus transthyretin levels by antisense oligonucleotide treatment', Amyloid, vol. 17, no. 2, pp. 43-49. https://doi.org/10.3109/13506129.2010.483121
Benson, Merrill ; Smith, Richard A. ; Hung, Gene ; Kluve-Beckerman, Barbara ; Showalter, Aaron D. ; Sloop, Kyle W. ; Monia, Brett P. / Suppression of choroid plexus transthyretin levels by antisense oligonucleotide treatment. In: Amyloid. 2010 ; Vol. 17, No. 2. pp. 43-49.
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