Key Takeaways:
- Researchers successfully used CRISPR base editing to correct a lethal liver disease (hereditary tyrosinemia type I) in mouse fetuses, with effects lasting into adulthood.
- Unlike traditional CRISPR, base editing alters single DNA nucleotides without cutting the genome, reducing risks of unintended mutations.
- Only 15% of liver cells needed correction to cure the disease, showcasing the method’s surprising efficiency.
- The procedure targeted the fetus’s liver via the vitelline vein, leaving the mother unharmed and avoiding off-target effects.
- While years from human trials, this approach could treat other congenital disorders (e.g., cystic fibrosis, metabolic diseases) diagnosed prenatally.
CRISPR Genetic Therapy Potential
Recently, a research team at the University of Pennsylvania and the Children’s Hospital of Philadelphia (CHOP) released a study focusing on the use of CRISPR genome editing technique, in which they were able to alter the DNA of laboratory mice in the womb, eliminating the potential of an often-fatal liver disease before birth. Although this research is years away from being able to utilize the CRISPR technique in human fetuses for the same purpose, it is a step in the right direction with potential.
CRISPR vs. Traditional Gene Therapy
This recent success suggests the possibility of genome editing’s use as an alternative to current gene therapy. In traditional gene therapy, an entire gene is affected, typically through the use of a virus to target cells that contain the disease-causing gene. By utilizing CRISPR, only the mutated part of the gene is changed. Think of it like buying a completely new car for a defective part rather than simply replacing that specific part. The reasoning for genetic therapy is simple: it prevents the negative, irreversible, or even fatal, effects of a disease.
The Study
Dr. Musunuru and his team of researchers focused on the applications of the CRISPR technique, targeting hereditary tyrosinemia type I, which is an inherited disease that damages the liver months before birth. Their methodology involved the removal of the fetus from a pregnant mouse and injection of CRISPR into the vitelline vein, specifically because it is near the surface of the amniotic sac and, more importantly, because it connects to the liver. They utilized a form of CRISPR called base editing, which changes an incorrect DNA nucleotide base, rather than the traditional form of CRISPR, which cuts DNA at the mutated location and inserts replacement nucleotides. This process doesn’t need to cut the DNA, preventing any complications resulting from the cutting process.
They first completed a trial run, using a gene called PCSK9, which is a protein involved in cholesterol level regulation in the bloodstream. In this trial, it only affected the liver as intended and had no effects on the mother. It also resulted in low cholesterol levels, demonstrating the base editing success. It is important to note that these results were seen even when only 15 percent of cells were affected, lasting through the animals’ adulthood.
They then used this base editor on a gene, HPD, related to hereditary tyrosinemia, and their results demonstrated disabling of the HPD gene. Similar to the trial study, only 15 percent of the liver cells were edited, and yet this was enough to cure the mice. They remained unaffected through adulthood. Although there are numerous other steps and research that must be done before this can be utilized in clinical research, these results are truly promising. The team hopes to apply this research to other severe congenital diseases, realizing that this research should simply be used as an additional tool, rather than a replacement for current gene therapy techniques.
FAQs:
How is base editing different from regular CRISPR?
Base editing changes a single DNA “letter” (nucleotide) without cutting the DNA strand, minimizing risks of errors. Traditional CRISPR cuts DNA and relies on the cell’s repair process, which can introduce mutations.
Why focus on the liver for this study?
The liver is crucial for metabolizing toxins. Hereditary tyrosinemia causes fatal liver damage shortly after birth, making it an urgent target. The vitelline vein also allows direct access in utero.
Is this safe for humans yet?
No. While successful in mice, human trials require extensive safety testing. Researchers must ensure no off-target edits and assess long-term effects.
What other diseases could this treat?
Congenital disorders diagnosed prenatally, such as phenylketonuria (PKU) or sickle cell anemia, where early correction could prevent lifelong complications.
When might this be available for humans?
Likely a decade or more. Regulatory hurdles, ethical considerations, and technical refinements (e.g., delivery methods) must be addressed first.
References
Rossidis, A.C., Stratigis, J.D., Chadwick, A.C. et al. In utero CRISPR-mediated therapeutic editing of metabolic genes. Nat Med 24, 1513–1518 (2018). https://doi.org/10.1038/s41591-018-0184-6
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