Gene Therapy by Liver Transplantation and Single Stranded Oligonucleotides (SSOs) in Familial Amyloidotic Polyneuropathy (FAP)

Abstract

Liver transplantation has been considered as a promising therapy to halt the progression of clinical symptoms of progression in familial amyloidotic polyneuropathy (FAP) because most of transthyretin (TTR) is produced by the liver. In addition, domino liver transplantation using an FAP patient's liver has been performed because of shortage of domor livers. However, the use of liver transplantation as therapy for familial amyloidotic polyneuropathy (FAP) has given rise to several problems, an alternative treatment is needed. We have tried several other approaches: To suppress production of variant transthyretin (TTR) in the liver, we injected purified normal human TTR into patients with FAP. Production of variant TTR levels decreased significantly for 48 h. However, 1 week after the injection, production returned to levels that were almost the same as those before injection. TTR has a rapid turnover, so this method cannot be used to suppress production of the harmful protein for an extended time. An RNA/DNA chimera and single-stranded oligonucleotides (SSOs) were tested in vitro and in vivo in an attempt to repair the amyloidogenic TTR gene in the liver and retina. On the basis of results achieved so far, SSOs is a promising tool for gene therapy.