Phenylketonuria (PKU) is a rare genetic disease that affects a small percentage of the population, causing an accumulation of the amino acid phenylalanine in the bloodstream. Uncontrolled PKU can lead to severe consequences, including intellectual disability, psychiatric issues, and seizures. Current therapies, while helpful, demand meticulous and lifelong adherence, posing a significant challenge for most patients.
New research from the Perelman School of Medicine at the University of Pennsylvania presents promising insights into potential future treatments for PKU, utilizing cutting-edge gene editing techniques, specifically prime editing and base editing. Two separate studies, one published in The American Journal of Human Genetics and the other in Human Genetics and Genomics Advances, shed light on groundbreaking findings.
These studies were presented at the American Society of Human Genetics (ASHG) annual meeting in Washington, D.C. The research, conducted by Dominique Brooks, a graduate student in the laboratory of Dr. Kiran Musunuru, a professor of Cardiovascular Medicine and Genetics at Penn, offers hope for individuals with PKU by exploring the possibilities of gene editing as a potential therapeutic avenue.Â
In the first study, researchers delved into a “prime editing” approach to correct the genetic variant responsible for PKU. Prime editing is often likened to a word processor for DNA, enabling precise changes by rewriting specific genetic sequences. The team examined 129 individuals with PKU, focusing on a specific genetic variant, c.1222C>T, in the phenylalanine hydroxylase (PAH) gene, which is the most common cause of PKU worldwide.
Individuals with this variant struggled to maintain healthy phenylalanine levels in their blood, which is crucial for PKU patients. They should maintain Phe levels within the range of 120-360 ÎĽmol/L to prevent neurological damage. Unfortunately, a majority of those studied had Phe levels exceeding this range.Â
The researchers conducted experiments on human liver cells with the problematic gene and successfully demonstrated the effectiveness of prime editing in correcting this variant. This finding holds the potential to open doors for therapeutic interventions. Furthermore, the research team extended their study to mice, utilizing prime editing in the liver to correct the same PAH c.1222C>T variant. This led to a substantial reduction in Phe levels, with all treated mice falling well below the critical threshold of 360 ÎĽmol/L. Notably, this correction did not affect the liver function of the mice.Â
Dr. Musunuru, a senior author of both studies, emphasized the significance of this research, stating that it brings hope for individuals with PKU. This lifelong condition, which currently lacks durable treatments, might find a solution in gene editing, offering the potential for permanent correction of the most common genetic variant associated with the disease.Â
The second study also centered on the most frequent genetic cause of PKU, the PAH c.1222C>T variant. Here, researchers explored base editing, a gene-editing technique that precisely modifies specific DNA sequences by replacing one DNA letter with another, akin to using a pencil and eraser. This technique was first tested in lab-grown liver cells and then in mouse models.Â
The results were remarkable. When the selected base editor and guide RNA were delivered to the mice through lipid nanoparticles, a technology similar to that used in COVID-19 mRNA vaccines, Phe levels were normalized within just 48 hours. Further studies indicated that these reductions in Phe levels remained sustained for up to one year, marking a significant breakthrough in PKU treatment. This is particularly promising, considering that PKU management typically involves lifelong efforts to control Phe levels.Â
Dr. Rebecca C. Ahrens-Nicklas, an assistant professor of Pediatrics at the Children’s Hospital of Philadelphia and a senior author of both studies, highlighted the significance of these findings in advancing PKU treatment. While the results from animal models are promising, additional research is needed to refine the base-editing approach and compare its effectiveness with other gene-editing methods.Â
Phenylketonuria (PKU) is a rare genetic disorder that affects a small segment of the population, posing significant challenges to those afflicted. Current treatments demand lifelong adherence and careful management, making the disease burdensome. However, recent research from the Perelman School of Medicine at the University of Pennsylvania offers newfound hope for individuals with PKU.Â
By harnessing the power of gene editing, specifically through prime editing and base editing, researchers have made substantial progress in addressing the genetic variants responsible for PKU. Prime editing allows for precise corrections to be made in the DNA, while base editing replaces specific DNA sequences with exceptional precision.
Both techniques have shown promise in correcting the most common genetic variant associated with PKU, potentially offering a permanent solution for affected individuals. The implications of this research are significant, as it offers a path towards more effective treatments for PKU, ultimately improving the lives of patients. While challenges remain, the possibilities of gene editing in PKU treatment mark a vital step forward in the quest for a durable solution to this rare genetic disease.Â
Journal Reference Â
The American Journal of Human Genetics (2023). Human Genetics and Genomics Advances (2023).Â
