ALN-HBV
Hepatitis B virus (HBV) infection is a global health problem. Eight HBV genotype (A-H) infections are all over the world, and A-D types will have corresponding clinical symptoms. Although there are currently vaccines that can prevent hepatitis B, according to the World Health Organization (WHO) survey results, there are still more than 250 million people worldwide infected with chronic HBV, with the risk of developing HBV-related liver complications, such as chronic hepatitis, cirrhosis and primary life-long hepatocellular carcinoma.
The current treatment for chronic hepatitis B is mainly long-term antiviral therapy, which can kill low levels of viral cells, but HBV virus will continue to exist and affect the treatment effect. Therefore, there is an urgent need for safe and convenient new treatments. Nowadays, targeting knockout of the hepatitis B surface antigen to restore the host's immune response, thereby achieving "functional cure" for HBV patients is considered the goal of any new therapy. ALN-HBV is a small-molecule RNA therapeutic agent for targeted gene silencing. It shows good therapeutic effects in rodent HBV infection models and is considered to be one of the commonly used drugs for the treatment of chronic hepatitis B infection in the future.
HBV Infection and RNAi Gene Therapy
HBV belongs to the hepatitis virus family, with a 3.2 kb circular, partially double-stranded DNA genome, which as a closed covalent circular DNA (cccDNA) can cause persistent infection symptoms in the hepatocyte nucleus. cccDNA encodes 7 HBV proteins, which are expressed by 5 major RNA transcripts, and they all share a common 3' end sequence. The viral genome is replicated by pregenomic RNA, which serves as a template for reverse transcription, also serves as the coding mRNA for the viral core and polymerase protein. The pre-C mRNA is initiated upstream of the pre-genomic RNA and used as a template for the production of the hepatitis B e antigen (HBeAg). HBsAg is incorporated into viral particles and subviral particles, resulting in virus-specific immune dysfunction, which is a sign of chronic HBV infection.
RNAi (RNA interference) is a revolution in the field of biology in recent years and represents a breakthrough in understanding how genes are turned on and off in cells, as well as a new approach to drug discovery and development. Small interfering RNA (siRNA) is a molecule that mediates RNAi, which can effectively control the pathogenic factors by silencing specific mRNA, thereby preventing the production of disease-causing proteins. ALN-HBV is an N-acetylgalactosamine cluster developed in the treatment of chronic hepatitis B infection combined with siRNA, targeting highly conserved sequences in HBV X ORF. The combination of GalNAc makes it possible to deliver siRNA to hepatocytes without any other specific delivery components.
Preclinical Studies of ALN-HBV
Results of preclinical studies in rodent HBV models indicate that subcutaneous injection of ALN-HBV can effectively and permanently knock out HBsAg. A single dose of ALN-HBV in mice resulted in a maximum reduction of HBsAg of 3.6 log10 after 15 days, with an average reduction of 1.6 log10. Multiple doses of ALN-HBV showed a highly durable knockout effect in rats, and the effect lasted up to 4 months after three weekly doses of 3 mg/kg ALN-HBV. In addition, in 13-week GLP toxicology studies in rats and non-human primates, ALN-HBV is generally well tolerated.
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