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A lipid nanoparticle is typically spherical with the size of around 80 nm in diameter which is much smaller than the commercial cationic liposome-based transfection reagent (several hundred nm).Another notable clinical program is ALN-VSP from Alnylam which is composed of LNPs containing two different siRNAs targeting vascular endothelial growth factor A (VEGF-A; for inhibiting tumor angiogenesis) and kinesin spindle protein (KSP; for inhibiting tumor mitosis).An siRNA drug, ARC-520, developed by Arrowhead Research, which contains hepatocyte-tropic cholesterolconjugated siRNAs targeting HBV coagulation factor VII and is delivered by Dynamic Poly Conjugate technology, has shown promising result in a Phase I clinical trial and has just entered a Phase II clinical trial.TKM-PLK1, an LNP formulated siRNA therapy from Tekmira, is in early clinical trials for adrenocortical carcinoma, gastrointestinal neuroendocrine tumors and hepatocellular carcinoma.In a Phase I clinical trial for ALN-VSP, promising results showed that siRNAs were delivered into the tumor and siRNA-mediated mRNA cleavage of VEGF-A and regression of liver metastases were observed in some patients.Patisiran, composed of synthetic siRNAs targeting TTR gene and delivered by LNPs, led to knockdown of serum TTR protein levels of up to 96% in a Phase II clinical trial.In particular, Alnylam and Tekmira, two leading RNAi therapeutic companies, have developed new generations of LNPs that are exceedingly efficient for delivering siRNAs into liver cells by intravenous administration.TKM-Ebola is a mixture of three siRNAs targeting three Ebola genes (delivered by LNPs) and has shown 100% protection of monkeys from deadly Ebola infections.Patisiran is the first FDA approved siRNA drug in the market in 2018.

A lipid nanoparticle is typically spherical with the size of around 80 nm in diameter which is much smaller than the commercial
cationic liposome-based transfection reagent (several hundred nm). Besides the advantage of size, the feature of containing cationic
lipid which is to bind to negatively charged siRNA also makes lipid nanoparticles better than other delivery vectors. In particular,
Alnylam and Tekmira, two leading RNAi therapeutic companies, have developed new generations of LNPs that are exceedingly efficient for delivering siRNAs into liver cells by intravenous administration.
The most advanced clinical program of siRNA drug is patisiran (ALN-TTR02) from Alnylam. Patisiran is designed to treat Transthyretin (TTR)-mediated amyloidosis which is an inherited disease caused by genetic mutations in the TTR gene. Patients carrying
the mutated TTR gene produce misfolded TTR proteins in the liver, which can aggregate to form amyloid fibrils in tissues such as the
peripheral nerves and heart. The resulting disease is polyneuropathy or cardiomyopathy which is progressively debilitating, and
often fatal. Patisiran, composed of synthetic siRNAs targeting TTR gene and delivered by LNPs, led to knockdown of serum TTR
protein levels of up to 96% in a Phase II clinical trial. Patisiran is the first FDA approved siRNA drug in the market in 2018.
Another important area for siRNA therapeutics is viral infection which traditionally lacks effective treatment options and has
huge impact on public health. The current pandemic of Ebola virus in West Africa and newly discovered coronavirus in Middle
East highlighted the urgent needs for effective anti-viral treatment for highly infectious and emerging viruses. For Ebola virus,
a siRNA drug, TKM-Ebola, is the most advanced Ebola therapy in clinical development (in Phase I trial). TKM-Ebola is a mixture
of three siRNAs targeting three Ebola genes (delivered by LNPs) and has shown 100% protection of monkeys from deadly Ebola
infections. siRNA drugs are also in development for treating chronic hepatitis B virus (HBV) infection, a disease prevalent in Chinese
populations. An siRNA drug, ARC-520, developed by Arrowhead Research, which contains hepatocyte-tropic cholesterolconjugated siRNAs targeting HBV coagulation factor VII and is delivered by Dynamic Poly Conjugate technology, has shown promising result in a Phase I clinical trial and has just entered a Phase II clinical trial.
For cancer therapy, siRNAs offer a quick way to design gene targeted and personalized therapy based on the rich knowledge in
cancer biology and oncogenes. One of the key clinical targets is polo-like kinase 1 (PLK1), a protein involved in cell cycle regulation
and often overexpressed in tumor cells. PLK1 is a well-validated pro-oncogene in multiple cancers including colon and lung cancer
cells. TKM-PLK1, an LNP formulated siRNA therapy from Tekmira, is in early clinical trials for adrenocortical carcinoma, gastrointestinal neuroendocrine tumors and hepatocellular carcinoma. Another notable clinical program is ALN-VSP from Alnylam which is
composed of LNPs containing two different siRNAs targeting vascular endothelial growth factor A (VEGF-A; for inhibiting tumor
angiogenesis) and kinesin spindle protein (KSP; for inhibiting tumor mitosis). In a Phase I clinical trial for ALN-VSP, promising
results showed that siRNAs were delivered into the tumor and siRNA-mediated mRNA cleavage of VEGF-A and regression of liver
metastases were observed in some patients.