Unlocking the Potential: CRISPR-Cas9 Gene Editing in Liver Diseases

Introduction to CRISPR-Cas9 gene editing
Liver diseases: The need for innovative treatments
CRISPR-Cas9 applications in liver disease
Precision medicine and personalized treatments
Future prospects and research directions
Further reading

CRISPR-Cas9 gene editing holds immense potential in the field of precision medicine for liver diseases. This innovative technology permits researchers to precisely modify genes linked to liver conditions, ultimately offering hope for targeted treatments.

​​​​​​​Image Credit: vchal/Shutterstock.com

Introduction to CRISPR-Cas9 gene editing

The science of genetic engineering has been revolutionized by the groundbreaking CRISPR-Cas9 gene-editing technique. This system differs from other methods by using RNA instead of a protein to identify DNA.

It is classified into three types that share essential components: the CRISPR array, the upstream leader sequence, and the Cas genes. The array consists of repetitive sequences, the leader region acts as a promoter for transcription, and the Cas genes encode Cas proteins that cleave the targeted DNA.

Recognition of the target  sequence is made possible through the protospacer-associated motif (PAM), a short sequence flanking the target site. The Cas9 protein, utilized in the commonly used Type II system, recognizes these PAM sequences.

Once the tracrRNA forms an RNA duplex with the crRNA (CRISPR-derived RNA), which is partially complementary to the CRISPR repeats, the complex detects and cleaves the DNA. After the DNA is cut, the natural repair mechanisms of the cell take control, allowing for precise modifications to the genetic code.

Since its discovery in 1987, the CRISPR-Cas9 gene-editing system has undergone a remarkable journey of development. The foundational work began with Yoshizumi Ishino, who first identified the unique repetitive DNA sequences in the genomes of bacteria. However, it wasn't until 2012 that CRISPR-Cas9's true potential was unveiled by Jennifer Doudna and Emmanuelle Charpentier.

In 2012, Doudna and Charpentier's research on the precise DNA editing capabilities of the CRISPR-Cas9 system gained widespread recognition. Their breakthrough discovery paved the way for the rapid adoption and advancement of CRISPR-Cas9 as a gene-editing tool, ultimately earning them the Nobel Prize in Chemistry in 2020.

Additional significant contributors to the development of CRISPR-Cas9 include Feng Zhang and David Liu. In 2018, Zhang and Liu demonstrated the precise and efficient editing of individual DNA or RNA bases that elevated the versatility and effectiveness of CRISPR-Cas9 in genetic engineering.

Liver diseases: The need for innovative treatments

Liver disease is a global health concern that encompasses a wide range of conditions such as viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), cirrhosis, and cancer. The prevalence of liver diseases has been steadily increasing in recent years, making it imperative to explore new therapeutic approaches.

These diseases can be caused by viral infections, alcohol consumption, obesity, autoimmune disorders, genetic and environmental factors. One example of a liver disease that has gained significant attention is NAFLD. It is closely associated with metabolic syndrome and ranges from simple fatty liver, which can progress to non-alcoholic steatohepatitis (NASH), fibrosis and eventually cirrhosis.

The increasing prevalence of obesity and metabolic disorders has contributed to the rising incidence of NAFLD worldwide.

Some of the current therapeutic strategies for the treatment of liver disease include targeted antiviral therapy for viral hepatitis; lifestyle modifications and pharmacotherapy for those conditions such as metabolic syndrome, obesity and insulin resistance that are associated with the development of NAFLD; immunomodulatory therapies for autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis that lead to liver inflammation; and ultimately liver transplantation in cases of severe liver disease or cancer.

While some therapies can alleviate symptoms and slow disease progression, they cannot address the full range of genetic, environmental, and lifestyle factors affecting each individual. To tackle this, researchers and healthcare professionals are actively seeking new approaches to enhance disease management and prevent liver-related complications.

CRISPR-Cas9 applications in liver disease

CRISPR-Cas9 has been of particular interest in the field of liver research. For example, hepatitis B virus (HBV)-associated diseases are primarily caused by the persistence of HBV covalently closed circular DNA (cccDNA) in hepatocytes. Current antiviral therapies (e.g. nucleos(t)ide analogs) are effective in inhibiting HBV replication, but are unable to eliminate cccDNA, making it a major barrier to eradicating chronic hepatitis B. 

Several studies have shown that the CRISPR-Cas9 system is capable of disrupting the intrahepatic HBV genome, with a significant reduction in serum surface antigen levels in an in vivo HBV model. Another study, targeting DNA polymerase κ (POLK), a key player in cccDNA formation, efficiently inhibited the conversion of relaxed circular DNA into cccDNA.

Other examples include hepatocellular carcinoma (HCC) and hereditary tyrosinemia type I (HTI).HCC studies have demonstrated the potential of CRISPR-Cas9 to target genes such as G9a, eEF2 kinase, NCOA5, CXCR4, ASPH and CDK7, which are involved in the development and progression of HCC. In the case of HTI, CRISPR-Cas9-mediated correction of the Fah (fumarylacetoacetate hydrolase) mutation in HTI mouse models improved the disease phenotype to a less severe form.

Gene Editing for Liver Disease Applications - The Liver Meeting® 2017

Precision medicine and personalized treatments

The most promising application of the CRISPR-Cas9 technology is in treating human diseases. While clinical applications are still in the early stages, there have been a growing number of preclinical trials targeting various human diseases.

CRISPR-Cas9 technology holds significant promise for enabling personalized treatment approaches for liver disease patients. Using the CRISPR screening technique combined with single-cell sequencing, researchers can gain a deeper understanding of the genetic heterogeneity within liver diseases.

CRISPR-Cas9 can be used to develop cell-based therapies for liver diseases. Researchers can use CRISPR-Cas9 to modify cells, such as immune cells or stem cells, and then transplant these modified cells back into the patient.

Importantly, by combining CRISPR-Cas9 with other technologies, such as gene expression monitoring or gene regulation circuits, it’s possible to design treatment approaches that can be fine-tuned and adapted based on the patient's response.

Future prospects and research directions

The CRISPR/Cas9 system has become a powerful genome-editing tool that enables large-scale function-based screens in mammalian cells. Cas9/sgRNA screens are a valuable tool for systematic genetic analysis.

The combination of CRISPR screening and single-cell sequencing can efficiently identify target genes and explore heterogeneity at the single-cell level. This approach is consistent with the concept of precision medicine.

Synthetic logic circuits based on CRISPR-Cas9 have also shown potential for controlling gene expression in cancer cells. In addition, AAV-based gene therapy using the all-in-one AAV-Cas9 system (FDA approved for preclinical studies) shows promise as a safe and effective means of targeting liver disease. These advances provide opportunities for tissue-specific gene modification and cell-based therapies.


Further reading

Last Updated: Nov 1, 2023

Deliana Infante

Written by

Deliana Infante

I am Deliana, a biologist from the Simón Bolívar University (Venezuela). I have been working in research laboratories since 2016. In 2019, I joined The Immunopathology Laboratory of the Venezuelan Institute for Scientific Research (IVIC) as a research-associated professional, that is, a research assistant.


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