Gene therapy: Lessons learned from liver transplantation for transthyretin-amyloidosis

✍ Scribed by Ole B. Suhr; Gösta Holmgren; Erik Lundgren

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 75 KB
• Volume: 10
• Category: Article
• ISSN: 1527-6465
• DOI: 10.1002/lt.20302

✦ Synopsis

Familial amyloidotic polyneuropathy is the common form of hereditary generalized amyloidosis and is characterized by the accumulation of amyloid fibrils in the peripheral nerves and other organs. Liver transplantation (LTx) has been utilized as a therapy for familial amyloidotic polyneuropathy because the variant transthyretin (TTR) is predominantly synthesized by the liver, but this therapy has several problems. Thus, we need to develop a new treatment that prevents the production of the variant TTR in the liver. In this study, we used HepG2 cells to show in vitro conversion of the TTR gene by singlestranded oligonucleotides, embedded in atelocollagen, designed to promote endogenous repair of genomic deoxyribonucleic acid. For the in vivo portion of the study, we used liver from transgenic mice whose intrinsic wild-type TTR gene was replaced by the murine TTR Val30Met gene. The level of gene conversion was determined by real-time RCR combined with mutant-allelespecific amplification. Our results indicated that the level of gene conversion was approximately 11 and 9% of the total TTR gene in HepG2 cells and liver from transgenic mice, respectively. In conclusion, gene therapy via this method may therefore be a promising alternative to LTx for treatment of familial amyloidotic polyneuropathy.