Researchers from Portugal talk about a new strategy for the treatment of amyloidosis, which is based on the control of the expression of the gene responsible for the production of transthyretin.

Patients treated with lipid-encapsulated small interfering RNA (siRNA) showed a 40% reduction in transthyretin levels compared to placebo after 7 days.

Normal (not mutated) transthyretin treatment affected the same extent.

Dr Teresa Coelho of Porto's St. Antonio Hospital said in a new issue of the New England Journal of Medicine that patients treated with second-generation siRNA achieved an 87% reduction in transthyretin levels..

“Our results suggest that the significant reduction in transthyretin levels that we observed in patients could reverse the course of the disease in patients with transthyretin amyloidosis.. The ability of second-generation drugs to reduce levels of mutant and normal transthyretin offers advantages over liver transplantation,” the authors concluded..

Although this was only a phase I study, the results are very encouraging and have a wide range of applications, including the treatment of Alzheimer's disease, cancer and several other diseases..

“This study, in my opinion, is a colossal breakthrough.. We hope the new drug will be available in the US. The study was conducted in Europe and the medicine is only approved there so far.. We very much hope that amyloidosis patients here in the States will be able to use this drug, ”commented Dr. Susanna Lench from Columbia University on the study..

Recall that to date, more than 100 variants of the gene encoding transthyretin have been discovered.. An excess of transthyretin as a result of such mutations can lead to the deposition of amyloid in peripheral nerves, the gastrointestinal tract, the heart, kidneys, meninges, and the vitreous body of the eye.. Amyloid is composed of mutated and normal transthyretin.

Liver transplantation is a treatment option for patients with familial amyloid polyneuropathy, but transplantation only addresses the problem of excess mutated transthyretin without affecting normal transthyretin production in the eyes and central nervous system.

Interest in the therapeutic potential of small interfering RNAs is related to the fact that siRNAs affect the control of gene expression.. The main obstacle to the clinical use of siRNA is the lack of safety data, as well as the lack of sufficiently effective methods of delivery.. Lipid nanoparticles have demonstrated the ability to deliver siRNA to hepatocytes, providing a persistent decrease in the expression of target genes.

ALN-TTR01 and ALN-TTR02 are lipid nanoparticles of the first and second generations, respectively, which are designed to transfer siRNA to target genes.. These carriers have similar physical and chemical properties, but differ in ionizable lipid components, which determine their effectiveness..

A comparative study of two types of carrier particles was carried out by an international team that included scientists from England, Sweden and Portugal. They randomized 32 patients with transthyretin amyloidosis into two groups - the first received a placebo, and the second received siRNA with ALN-TTR01.. Additionally, 17 healthy volunteers who received placebo or ALN-TTR02 participated..

The researchers report that both agents resulted in a " At the maximum dose of 1.0 mg/kg, ALN-TTR01 caused the maximum therapeutic effect - a 38% reduction in transthyretin levels compared with placebo on the seventh day (P \u003d 0.01). At a dose of 0.15-0.30 mg/kg, ALN-TTR02 resulted in a reduction in transthyretin levels of 82.3-86.8% compared with placebo (P\u003c0.001). On day 28, transthyretin levels remained 56.6-67.1% below baseline (P\u003c0.001).

The most common adverse events were intravenous drug reactions, which occurred in 20.8% of patients on ALN-TTR01 and 7.7% of patients on ALN-TTR02..

Despite the enthusiasm, Dr. Maury Gertz of the Mayo Clinic (Rochester, USA) said that these are only preliminary results obtained on a small number of patients.. According to him, this study has so far only shown the fundamental possibility of such an approach to the treatment of amyloidosis..

He believes that to prove the therapeutic efficacy of siRNA, the next study is required, during which patients will receive the drug for a long time - this is the only way to understand how the drug affects the course of amyloidosis..

medbe. en.