**5.1 IDOX, doxycycline, and RNAi therapy**

Since the difficulties associated with liver transplantation prevented adequate treatment of FAP patients, new non-surgical treatment methods were researched. It was initially shown that 4′iodo′4′-doxy-doxorubicin (IDOX) inhibits amyloid formation and promotes the resorption of amyloid deposits. Initially shown that IDOX can induce amyloid resorption in patients with immunoglobulin light chain amyloidosis, it was further studied for all types of amyloid deposition disorders. It is hypothesized that IDOX exerts its effects by inhibiting fibril growth and increasing the solubility of amyloid deposits. This, in turn, facilitates amyloid clearance. These results have been consistent in both in vivo and in vitro studies through two distinct binding sites between IDOX and amyloid fibrils [52].

At around the same time as IDOX was being investigated, Doxycycline became the next promising medication that showed similar success in both FAP transgenic mice and phase II human trials with transthyretin amyloidosis. It's theorized mechanism of action involves amyloid fibril destructuration and promotion of amyloid deposition. In one phase II trial, doxycyclin plus tauroursodeoxycholic acid resulted in stable cardiac and neuropathy symptoms after 1 year of treatment. When used in conjunction with TTR stabilizers, therapy could both block formation and promote clearance of existing amyloid simultaneously [53, 54].

The most recent research for transthyretin amyloidosis treatment has surrounded RNA interference (RNAi) therapy. RNAi therapy decreases transthyretin production from the liver by directly suppressing mRNA transcription of the gene that codes for the transthyretin protein. Due to the specific nature of this pharmacology, long-term side-effects of RNAi therapy have not been reported. Two medications, Patisiran and Inotersen, have become FDA approved in the past 5 years after studies have shown a dose-dependent reduction of both mutant and nonmuntant tranthyretin production and deposition. This RNAi therapy has been shown to cause between 50 and 80% reduction in transthyretin levels as early as 2–3 weeks after therapy initiation. Furthermore, these medications have provided significant neurologic symptomatic benefit in a majority of patients when compared to placebo therapy. Since these medications affect both mutant and nonmutant transthyretin production, they have been shown to not only have decreased side-effects to liver transplantation, but better long-term efficacy. The most common side effect to the medication reported has been transfusion-related reactions in 8–20% of patients [49, 55, 56].
