Beam Therapeutics announces new preclinical data

Beam Therapeutics Inc. (Nasdaq: BEAM), a biotechnology company developing precision genetic medicines through base editing, today announced new preclinical data demonstrating the potential of the company’s multiplex base editing approach to both reduce viral markers – including hepatitis B surface antigen (HBsAg) expression – and prevent viral rebound of hepatitis B virus (HBV) in in vivo models. The data will be presented today, September 19, 2022, in partnership with Fabien Zoulim’s laboratory at the INSERM Cancer Research Center of Lyon, during a poster presentation titled, “Cytosine base editing inhibits Hepatitis B Virus replication and reduces HBsAg expression in vitro and in vivo,” at the 2022 International HBV Meeting.

HBV causes serious liver infection that can become chronic, increasing the risk of developing life-threatening health issues like cirrhosis, liver failure or liver cancer. Chronic HBV infection is characterized by the persistence of covalently closed circular DNA (cccDNA), a unique DNA structure that forms in response to HBV infection in the nuclei of liver cells. Additionally, the HBV DNA integrates into the human genome, becoming a source of HBsAg. While currently available treatments can limit HBV replication, they do not inactivate these HBV genomic elements, which can lead to reinfection and reactivation of the HBV virus. This inability to prevent HBV infection rebound is a key challenge to curing HBV.

Base editors are designed to enable direct and irreversible conversion of a specific DNA base into another without inducing double-stranded breaks. In HBV infected cells, cytosine base editors (CBEs) can target both integrated HBV DNA and the cccDNA minichromosome at multiple locations, introducing precise and permanent stop codons in the viral genome. These stop codons are intended to silence the viral genes without the risk of chromosomal rearrangements that can arise with nuclease editing systems that create double-stranded breaks in DNA.

“Chronic HBV infection remains a major global health problem, and despite available antiviral medications, there is a significant need for a treatment that can both prevent viral replication and reduce viral protein expression,” said Giuseppe Ciaramella, Ph.D., president and chief scientific officer of Beam. “We are very excited to share these new data, highlighting the ability of our multiplex base editing approach to address both of these disease drivers of HBV infection in in vivo models for the first time. By preventing viral replication and silencing viral protein expression, this approach could represent a potentially curative option for the millions of people with HBV around the world. We look forward to continuing to explore its utility in additional preclinical studies.”

The data announced today build on previously shared in vitro data, which demonstrated the ability of HBV-targeting gRNAs and mRNA-encoding CBEs to introduce stop codons in HBV DNA leading to a substantial reduction of relevant HBV viral markers (HBsAg, HBeAg, HBV DNA, 3.5kb RNA). Based on those findings, Beam evaluated its approach in vivo in an HBV minicircle mouse model, with mice receiving one or two doses of the base editing reagents (mRNA & gRNA formulated into a lipid nanoparticle (LNP)), the antiviral treatment entecavir or control. Findings show that:

  • Base editing treatment led to a sustained >2 log10 IU/ml reduction of HBsAg observed in both LNP dose groups, compared to entecavir or control mice, in which no meaningful reductions were observed.
  • Base editing treatment led to sustained 3 log10 copies/ml reduction in serum HBV DNA with no HBV viral rebound observed compared to the entecavir group in which serum HBV DNA was reduced following administration but rebounded after entecavir treatment was discontinued.

Taken together, the findings demonstrate that base editing has the potential to permanently inactivate cccDNA and integrated HBV DNA by introducing mutations that prevent HBV replication and silence viral protein expression.

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