New therapeutic approaches for familial amyloidotic polyneuropathy (FAP)

Because 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 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. Recent studies suggested that certain metal ions affect amyloidogenesis. Among metal ions tested in an in vitro amyloid formation study, Cr3+ increased stability of both normal and mutant TTR tetramers and suppressed TTR amyloidogenesis induced by low pH. Our findings indicate that Cr3+ acts to suppress TTR amyloidogenesis. (Trans, trans)-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB), a Congo red derivative that binds to amyloid fibrils in FAP, as well as to those in senile plaques in Alzheimer's disease, effectively suppressed TTR amyloid formation in vitro. BSB may thus be useful for preventing amyloid formation. Free radical scavenger therapy was also tried with FAP patients but yielded no conclusive results. Finally, 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 are a promising tool for gene therapy.