ALN-TTR01
Transthyretin (TTR) protein functions as a transporter of retinol and thyroxine, and is produced primarily by the liver (> 95%). Transthyretin amyloidosis (ATTR) is a rare disease resulted from the deposition of hepatocyte-derived transthyretin amyloid in the peripheral nerves and the heart. Nowadays, an effective therapeutic approach based on RNA interference (RNAi) could reduce the expression level of transthyretins. ALN-TTR01, has been developed as a systemically delivered RNAi therapeutic that exploits first-generation lipid nanoparticle (LNP) technology, for ATTR disorders. To determine the activity and relative potency of this formulation in declining transthyretin levels, investigations in nonhuman primates and two sequential Phase I trials are being performed for more information.
ATTR Introduction
TTRs are associated with the formation of amyloid fibrils, resulting in TTR-related amyloidosis, in which the fibril proteins are deposited into different tissues and organs (e.g. gastrointestinal tract, peripheral nerves, heart, and kidneys), preferentially the nervous and cardiac system, leading to their inherent dysfunction. TTRs are also synthesized by the retina and choroid plexus, causing vitreal and leptomeningeal deposits. At least 100 genetic variants of the gene encoding TTRs are implicated in autosomal dominant formats of the disease, known as familial amyloidotic cardiomyopathy and familial amyloidotic polyneuropathy. The most common mutation related to familial amyloidotic cardiomyopathy is V122I, while the predominant mutation related to familial amyloidotic polyneuropathy is V30M.
ALN-TTR01 in Clinical Trials
RNAi is a well-recognized endogenous mechanism for controlling gene expression in which small interfering RNAs (siRNAs) that bind to the RNA-induced silencing complexes (RISCs) mediate the cleavage of targeted mRNAs. The capacity to transform siRNAs into available drugs has relied on the chemical processes that confer drug-like properties and promote safe, effective delivery to targets. The formulations of LNPs have emerged as an agent to transport siRNAs to hepatocytes and have generated a robust, durable reduction (called knockdown) in the genetic expression of several hepatocyte targets across many species. Here, ALN-TTR01 is an RNAi therapeutic against TTRs for the treatment of ATTR.
Figure 1. Efficacy of ALN-TTR01 in patients with transthyretin amyloidosis. (Coelho, 2013)
- Mechanism of action
ALN-TTR01 is the first-generation formulation of LNPs as agents to deliver siRNAs. The formulation has similar physicochemical characteristics but diversified ionizable lipid components, that are important determinants of potency. Each formulation encapsulates an identical siRNA that targets a conserved sequence in the 3' untranslated position of mutant and nonmutant mRNA in TTR, thus affecting the form of TTR. The final results from the Phase I clinical trial with ALN-TTR01 have been announced by its sponsors. The study data illustrated that the administration of ALN-TTR01 could result in considerable reductions in serum TTR levels, including both wild-type and mutant TTR proteins of ATTR patients.
- Clinical trials
ALN-TTR01 is an investigational novel drug that is being studied to treat ATTR amyloidosis. The purpose of current research is to verify if a single dosage of ALN-TTR01 is safe and can be tolerated without any side effects. This involves the side effects of ALN-TTR01 to confirm how much of the drug could be safely administrated to patients with ATTR amyloidosis. Additionally, the amount of ALN-TTR01 that gets into the blood and urine will be observed after study drug dosing, and whether the study drug lowers TTR protein levels in the blood.
After identifying a potent anti-TTR siRNA, ALN-TTR01 was employed in a single-dose, placebo-controlled Phase I trial to evaluate effect and safety on TTR levels. ALN-TTR01 was identified (at doses of 0.01-1.0 mg/kg of body weight) in 32 patients with ATTR amyloidosis. The rapid, dose-dependent, and durable reduction of TTR levels were shown in the trials. At a dose of 1.0 mg/kg, ALN-TTR01 inhibited TTR productions, with a mean reduction at day 7 of 38%, by comparison to the placebo group. The expression levels of mutant and nonmutant forms of TTRs were decreased to a similar extent. The declines were displayed to be RNAi-mediated.
Tab.1 Baseline characteristics of the study participants. (Coelho, 2013)
ALN-TTR01 suppressed the production of both forms of TTR proteins, building the proof of concept for RNAi therapy targeting mRNA transcribed from a disease-causing gene. Today results from Phase I clinical trial of ALN-TTR01 presented that the administration of ALN-TTR01 causes statistically significant decreases in serum TTR protein levels. Gene knockdown of TTRs was found to be rapid, dose-dependent, and durable after a single dosage. As a reliable expert in the gene therapy market, Creative Biolabs is committed to facilitating the development of siRNA-based therapeutics and dissecting the latest advancement of RNAi mechanisms. If you want to know more about gene therapy or siRNA custom services, please directly contact us or send an e-mail with your specific request.
Reference
- Coelho, T.; et al. (2013). Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013, 369(9): 819-829.
