[Gene therapy in familial amyloidotic polyneuropathy by single-stranded oligonucleotides (SSOs)]

Transthyretin (TTR) related familial amyloidotic polyneuropathy (FAP) is the common form of hereditary generalized amyloidosis and is characterized by the accumulation of amyloid deposits in the peripheral nerves and other organs. Liver transplantation has been utilized as therapy for FAP, because the variant TTR is predominantly synthesized by the liver, but this therapy is associated with several problems. Since we need to develop a new treatment, we examined the feasibility of gene therapy in FAP to prevent the production of variant TTR in the liver by using single-stranded oligonucleotides (SSOs). To examine in vitro and in vivo conversion of the TTR gene by SSOs embedded in atelocollagen, we used HepG2 cells and liver from transgenic mice whose intrinsic wild-type TTR gene was replaced by the mouse TTR V30M gene. The level of gene conversion was determined by real-time RCR combined with mutant-allele-specific amplification. The level of gene conversion was approximately 11% and 9% of the total TTR gene in HepG2 cells and liver from transgenic mice, respectively. Therefore, gene therapy via this method may be a promising alternative to liver transplantation for treatment of FAP.