Saint Jude finds new way to define ‘safe haven’ for gene therapies

Newswise – (Memphis, TN – September 22, 2022) Scientists at St. Jude Children’s Research Hospital have created a tool that can find safe places to insert genes into human DNA. The tool is an early step in the process of improving the safety and efficacy of gene and cell therapies. Today’s work appears in genome biology.

“We created Google Maps for genome editing,” said co-author Yong ChengJude, MD, Department of Hematology. “With this tool, we are introducing a new approach to identifying places to safely incorporate the gene strand. We have created step-by-step directions, so you can follow the steps and easily find safe haven sites in specific wipes.”

Gene therapy, in which a patient is given a functional copy of a dysfunctional gene, has shown success in treating some genetic disorders. However, this field has faced safety issues, including unintended activation of the oncogenic agent that has resulted in cancer in some patients. In response, the domain searched for “safe haven sites” – places in the genome where a gene could be inserted without causing cancer or other problems. Scientists have created a pipeline that uses genomic and epigenetic information from specific tissues, such as blood cells, to find sites of safe haven.

A new way to find safe haven sites

The tool compares highly variable DNA sequences between healthy people, using data from the 1000 Genomes Project. If a region of DNA is often deleted or inserted in healthy people, the researchers conclude that it is also likely to be safely altered by gene therapy.

“Our method is a novel approach to identifying genomic safe haven sites in a tissue-specific manner,” Cheng said. Nobody has tried it from this angle. Our first step was to find genetic loci that show a high frequency of insertions or deletions among healthy individuals.”

If the DNA in one cell were a chain, it would be two meters long. But in addition to linear sequencing, DNA can be transformed into complex three-dimensional structures using chromatin, the proteins attached to DNA, to fit into the cell. Just like a thread, DNA can have loops that affect its function. Take the St. tool. Jude consider the presence of these loops and other structures when searching for accessible safe haven sites.

“Our tool evaluates the three-dimensional structure of DNA, because human DNA is not a one-dimensional linear structure, it is actually three-dimensional,” Chen said. “Therefore, parts of the DNA may be far apart in the linear sequence of DNA but may be physically next to each other due to the loops of the 3D structure. In this case, the 3D proximity is more important than the linear distance.”

Balancing safety and therapeutic gene expression

“Safe gene therapy requires two things,” Cheng said. “Number one, maintaining high expression of the new gene. Second, the integration should have minor effects on the normal human genome, which is a major concern for people doing gene therapy.”

The scientists found that genes placed in the sanctuary sites identified by their tool maintained their expression over time. The researchers also showed that if they placed a gene at one of the safe haven sites identified by their tool, it affected genes nearby less than the classic safe harbor site.

The tool, called Secure Guided Genome and Epigenetics Mapping (GEG-SH), is freely available at https://github.com/dewshr/GEG-SH.

Authors and Funding

The study’s first authors are Dewan Shrestha, of the University of Tennessee’s St. Jude and Health Sciences Center, and Ishi Bagh of Rutgers, New Jersey State University. Other authors of the study are

Ruikyong Wu, Sheng Tang, and Qian Chi from Saint Jude; However, Zhang and co-author Jinchuan Xing, of New Jersey State University, Rutgers.

The study was supported by grants from the National Cancer Institute (P30 CA021765), the National Institutes of Health (R35GM133614), St. ALSAC, St. Jude’s fundraising and outreach organization.

St. Jude Children’s Research Hospital

St. Jude Children’s Research Hospital leads the way the world understands, treats and treats childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated comprehensive cancer center that is intended for children only. Treatments developed at St. Jude’s Hospital have helped increase the childhood cancer survival rate from 20% to 80% since the hospital opened 60 years ago. St. Jude freely shares her accomplishments, and every child saved on St. Jude means that doctors and scientists around the world can use this knowledge to save thousands of other children. Families never receive a bill from St. Jude for treatment, travel, housing and food – so families can focus on helping their children survive. To find out more, visit stjude.org Or follow Saint Jude on social media at Tweet embed.