ALN-TTRSC
Transthyretin-mediated (ATTR) amyloidosis is a form of systemic amyloidosis caused by amyloid deposits originated from a protein termed transthyretin (TTR). There are two types of ATTR amyloidosis, hereditary (ATTRv) and non-hereditary (ATTRwt, acquired) forms. Today, RNA interference (RNAi) therapeutics are believed to represent an attractive new approach for the treatment of ATTR amyloidosis, with the capacity to make a meaningful influence on patients with this progressive and fatal disease. Here, ALN-TTRSC (trade name: Revusiran) is designed and synthesized as a robust small interfering RNAs (siRNAs) based on RNAi mechanisms, offering a new and promising therapeutic option for ATTR patients.
ATTR Amyloidosis
TTR is a class of protein primarily produced by hepatocytes (liver cells). ATTR is a kind of disease induced by the accumulation of TTR amyloid fibrils in numerous body tissues. Cardiac and neuronal extracellular deposition of these substances leads to life-threatening cardiomyopathy (heart disease) or debilitating neuropathy. TTR cardiac amyloidosis results from the deposition of liver-derived mutant or wild-type TTR in the myocardium, resulting in heart failure and death. The hereditary type, also known as familial amyloidotic cardiomyopathy (FAC), is estimated to have an impact on at least 40,000 people around the world. Following symptom onset, the quality of life is largely affected and the disease proceeds irreversibly to death. Currently, available treatment options are limited and patients are severely managed with supportive care to alleviate heart failure symptoms. There're no approved therapies for TTR cardiac amyloidosis and there exists an urgent need for effective approaches to treatment.
Figure 1. Pathogenesis and clinical manifestations of ATTR amyloidosis. (Ibrahim, 2019)
ALN-TTRSC in Clinical Trials
RNAi is a naturally occurring cellular mechanism for controlling gene expression that is mediated by siRNA molecules. It's an extraordinary regulatory pathway that can trigger sequence-specific gene silencing within cells. If harnessed properly, RNAi could bring about a robust targeted therapeutic modality with clinical applications ranging from viral diseases to deadly cancers. Remarkably, siRNAs can be designed to specifically target endogenous disease-related genes. TTR mRNAs, as the first study of ALN-TTRSC in TTR cardiac amyloidosis, the therapeutic hypothesis for this siRNA-based treatment is that downregulating serum TTR protein via the inhibition of hepatic production may give rise to clinical benefit.
Figure 2. Schematic representation of a gene-silencing pathway. (Sioud, 2004)
- Mechanism of action
ALN-TTRSC is a subcutaneously administered RNAi therapeutic, composed of a siRNA directing both mutant and wild-type TTR mRNAs. The siRNA fragment is conjugated to a GalNAc (N-acetylgalactosamine) ligand, enabling receptor-mediated delivery to the hepatic tissues through the asialoglycoprotein receptor present on hepatocytes. In non-human primates, repeat-dose subcutaneous administration of ALN-TTRSC induced valid and sustained repression of serum TTR proteins, with about 80% decline observed at concentrations as low as 2.5 mg/kg. In single- and multidose pre-clinical safety assays, ALN-TTRSC was demonstrated to be commonly safe and well-tolerated at concentrations as high as 300 mg/kg in non-human primates.
- Clinical trials
In 2013, in Phase I, a randomized, double-blind, single and multi-dose, dose-escalation study has been initiated in normal healthy volunteers with up to 40 participants to evaluate the safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of administered ALN-TTRSC before the further development. In the multi-dose stage, participants received five daily doses as induction followed by five additional weekly doses for maintenance. The PD effects of ALN-TTRSC was monitored by serial measurements of serum TTR proteins.
Presently, ALN-TTRSC is in Phase II clinical trials for the treatment of ATTR patients with TTR cardiac amyloidosis. Preliminary data from the pilot Phase II trial illustrated potent and stable knockdown of serum TTR levels and seemed to be usually well-tolerated in most patients with TTR cardiac amyloidosis out to 10 months of treatment. The time is the longest human dosing experience for a GalNAc-siRNA conjugate recorded to date. Moreover, the trial will analyze preliminary clinical activity as measured by knockdown of serum TTR proteins and additional exploratory assays, such as cardiac imaging, circulating cardiac markers, six-minute walk tests, and measures of heart failure symptoms and quality of life.
The ability of siRNAs to silence gene expression in somatic mammalian cells is being a novel tool to block the expression of disease-causing genes. Researchers are looking forward to sufficient data from the ongoing Phase II studies with ALN-TTRSC, and continue to devote to improving the lives of patients with ATTR amyloidosis. These promising siRNA investigational therapeutics may halt progression in ATTR patients and provide potential treatment options for the management of this disease. 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.
Referencea
- Ibrahim, R.B.; et al. (2019). Contributions of animal models to the mechanisms and therapies of transthyretin amyloidosis. Front Physiol. 10: 338.
- Sioud, M. Therapeutic siRNAs. (2004). Trends Pharmacol Sci. 25(1), 22-28.