Suppression of choroid plexus transthyretin levels by antisense oligonucleotide treatment

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 (50 μg or 75 μg per 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.

Keywords:

• Amyloidosis
• transthyretin
• choroid plexus
• intracerebral haemorrhage
• dementia
• hydrocephalus

Abbreviations
TTR	=	transthyretin
ASO	=	antisense oligonucleotide
OLT	=	orthotopic liver transplantation
CSF	=	cerebral spinal fluid

Abbreviations
TTR	=	transthyretin
ASO	=	antisense oligonucleotide
OLT	=	orthotopic liver transplantation
CSF	=	cerebral spinal fluid

Acknowledgements

This work was supported by NIH grants PHS AG10133, DK42111, and RR-00750, Veterans Affairs Medical Research, the Marion E. Jacobson Fund, the Machado Family Research Fund; and by, the following donors to the Center for Neurologic Study: Basil Witt, Daryl Smith, Roasalie and Samuel Roxburgh and the Thagard Foundation.