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Editing genes before birth as a new therapy

Editing the PCSK9 gene in mice resulted in reduced cholesterol levels, a heart disease risk factor. After modification of a gene Hpd involved in hereditary tyrosinemia mice developed with no signs of the disease.

Image Credit: Photo by Volodymyr Hryshchenko on Unsplash

Although the term ‘gene editing’ may sound like science fiction, it isn’t! CRISPR-mediated gene editing is a technology first developed in the 1990s that enabled scientists to target and modify particular genes without damaging the whole genome. For example, they could modify crops to make them more resistant to diseases or parasites without affecting nutritional value or safety. Molecular biologists use CRISPR to study relationships between genes and how living things look and function. In medicine, this technology gives hope for creating new treatments to cure diseases that are currently incurable.

A cell’s DNA contains genes which encode all the information about how that cell is built and how it functions. CRISPR allows us to make changes to that DNA, and change how the cell functions. It is possible to turn off a particular gene by cutting it with an enzyme at its specific location on the long DNA molecule called the chromosome. Those enzymes are introduced into cells using a specially designed carrier, called a vector. Vectors are usually viruses that don’t cause disease.

One way of using gene editing is to identify and deactivate genes that are causing diseases. That includes genes that increase the risk of a disease, or normal genes that, when mutated or dysfunctional, cause genetic diseases.

Of course, no technology is perfect. There are always obstacles to overcome. Some of the genetic diseases that are potential candidates for gene editing treatment are lethal, which means that a child with a flawed gene is lost during pregnancy or shortly after birth. In these cases, treatment after birth is impossible. The immune system can also interfere with gene editing. Vectors, though harmless, can be still recognized by our immune system as foreign organisms, triggering defense mechanisms which disturb treatment.

In this study, the researchers wanted to see whether it is possible to mitigate symptoms of disease by modifying specific genes in mice before they are born. At the early stages of development, the cells are easier to modify and they divide at high rates. So, by modifying one cell, we change all cells that arise from it. Because embryos are small, less vector is needed to get the desired effect. Recognizing those benefits, the researchers then decided to try modifying two genes. One plays a role in heart disease risk and the other controls a genetic disorder called hereditary tyrosinemia type 1 (HT-1).

The first gene, called Pcsk9, is involved in the metabolism of cholesterol. Cholesterol isn’t all bad – it helps keep our cell membranes stable. But, high levels of cholesterol puts a person at risk for cardiovascular diseases such as coronary heart disease. Blocking the Pcsk9 gene decreases cholesterol.

Using CRISPR-mediated gene editing, the researchers blocked the Pcsk9 gene in mice embryos halfway through the pregnancy. After the modified mice were born, they observed decreased levels of the Pcsk9 protein and lower cholesterol during the first 3 months of life compared to mice that were not modified. They achieved these results without causing damage to the liver, where the majority of cholesterol is metabolized. In mice that were modified after birth, rather than as an embryo, the effects lasted only for 1 month. These mice produced more antibodies against the viral vector, hindering the treatment success.

Next, the researchers wanted to test their method on a hereditary tyrosinemia type 1 that, without early treatment, is fatal. This disease is caused by a mutation in a gene called Fah, causing a build-up of an amino acid called tyrosine and along with its toxic metabolites. Standard therapies decrease levels of toxic metabolites by suppressing a protein encoded by another gene called Hpd.

In this study, scientists used CRISPR-mediated gene editing to turn off the Hpd gene before birth. They modified mice embryos that had HT-1, abstained from giving them treatment and compared the results with mice that were not modified. Their study showed that unmodified mice died before the first month of life, whereas modified mice had developed properly for 3 months. The results were better than those seen in mice with HT-1 that receive standard treatment. Again, the liver (which is also responsible for tyrosine metabolism) of the modified mice did not show signs of damage caused by gene editing.

This study shows that introducing treatment before birth is effective in decreasing cholesterol levels and improving survival in mice with hereditary tyrosinemia. The effects also last longer than current treatments. Additionally, CRISPR editing does not damage the liver, which is a problem with current treatments. Scientists still need to understand how to translate these techniques from mice to humans in order to start clinical trials. They also want to make sure it is completely safe before actual treatments can be developed. One thing is for sure. We will definitely hear the term ‘gene editing’ a lot in the following years.

Study Information

Original study: In utero CRISPR-mediated therapeutic editing of metabolic genes

Study was published on: October 2018

Study author(s): Avery C. Rossidis, John D. Stratigis, Alexandra C. Chadwick, Heather A. Hartman, Nicholas J. Ahn, Haiying Li, Kshitiz Singh, Barbara E. Coons, Li Li, Wenjian Lv, Philip W. Zoltick, Deepthi Alapati, William Zacharias, Rajan Jain, Edward E. Morrisey, Kiran Musunuru, and William H. Peranteau

The study was done at: The Children’s Hospital of Philadelphia (USA), University of Pennsylvania (USA)

The study was funded by: United States National Institute of Health (NIH), National Center for Advancing Translational Sciences of the NIH, Institute for Translational Medicine and Therapeutics at the University of Pennsylvania, UPenn Orphan Disease Center; the Winkelman Family Fund in Cardiovascular Innovation

Raw data availability: Unknown if available

Featured image credit: Photo by Volodymyr Hryshchenko on Unsplash

This summary was edited by: Gina Misra