Genomic safe harbors (GSH) are regions of the human genome that have been identified and designated as safe landing sites for new therapeutic genes. These areas are free from other genetic elements that could potentially cause problems if they were to interact with the new gene. By using GSHs, scientists can ensure that any changes made to a cell’s genome will be limited to the desired area and will not cause any unintended consequences.
Today Harvard University shared a report on Phys.org to announce that a group of people who study genetics at Harvard’s Wyss Institute and the ETH Zurich in Switzerland have found safe spaces in the genome. This is to put new genes in without changing other parts of the genome that could be bad for patients.
What are genomic safe harbors (GSHs)?
GSHs could potentially be used to accommodate new gene therapies safely. For example, if a patient is suffering from a genetic disease, scientists could use GSHs for the insertion of healthy copies of a therapeutic gene into the patient’s genome. This would allow the patient to produce the correct protein needed to treat their disease. GSHs could also be used to correct genetic mutations that are responsible for causing cancer.
While GSHs offer a promising way to deliver new gene therapies safely, more research is needed to determine the best way to use them. Scientists still need to figure out which areas of the genome are safe to modify and how best to insert new genes into cells. There is also the risk that GSHs could be used to create ‘designer babies’ by altering genes in a way that could improve or change specific characteristics. For this reason, it is crucial to ensure that any changes made to the genome using GSHs are safe and reversible.
A group of scientists at Harvard’s Wyss Institute for Biologically Inspired Engineering, Harvard Medical School (HMS), and the ETH Zurich in Switzerland has created a new approach to assess landing sites with a higher chance for success for the safe insertion of therapeutic genes and their durable expression across many cell types. Two out of 2,000 GSH sites could be verified with adoptive T cell therapies, for instance, as well as Vivo gene therapy for diseases that could affect people’s skin. By designing GSH sites to deliver a reporter gene in T cells, as well as a therapeutic gene in skin cells, they demonstrated safe and long-lasting expression of the newly introduced genes.
Also interesting: David R. Liu – Can We Cure Genetic Diseases by Rewriting DNA?
Researchers have developed a way to find safe places in the human genome where new genes can be inserted without causing other unintended changes. They did this by studying 2000 different places in the genome and then testing two of them. They showed that new genes could be safely expressed in cells using these sites. The next step will be to use this information to create safe gene therapies for diseases like cancer. This is an important step forward in gene therapy and will help us to avoid any harmful side effects. Genomic safe harbors provide a way to insert new genes into the genome safely, and this technology could be used in the future to treat many different diseases.
Insight from within the research team
Key individuals in this research shared their views on the report. “While GSHs could be utilized as universal landing platforms for gene targeting, and thus expedite the clinical development of gene and cell therapies, so far no site of the human genome has been fully validated. All of them are only acceptable for research applications,” adds Wyss Core Faculty member George Church, Ph.D., a senior author on the study. “This makes the collaborative approach that we took toward highly-validated GSHs an important step forward. Together with more effective targeted gene integration tools that we develop in the lab, these GSHs could empower a variety of future clinical translation efforts.”
“In this step-by-step whole-genome scan, we computationally excluded regions encoding proteins, including proteins that have been involved in the formation of tumors, and regions encoding certain types of RNAs with functions in gene expression and other cellular processes. We also eliminated regions that contain so-called enhancer elements, which activate the expression of genes, often from afar, and regions that comprise the centers and ends of chromosomes to avoid mistakes in the replication and segregation of chromosomes during cell division,” said first-author Erik Aznauryan, Ph.D. “This left us with around 2,000 candidate loci all to be further investigated for clinical and biotechnological purposes.”
The team looked at two GSH sites in human cells that are of particular interest for cell and gene therapies. They investigated these sites in immune T cells and skin cells, respectively. T cells are used in many adoptive cell therapies to treat cancer and autoimmune diseases. These therapies could be safer if the receptor-encoding gene was stably inserted into a GSH. Also, skin diseases caused by harmful mutations in genes controlling the function of cells in different skin layers could potentially be cured by the insertion and long-term expression of a healthy copy of the mutated gene into a GSH of dividing skin cells.
The investigated GSH site in the T cell genome is located in a region known as the “safe harbor” for insertional mutagenesis. This term refers to the low risk of causing cancer or other harmful changes in cells when new genes are inserted into this site. The team found that, even when the receptor-encoding gene was inserted into this safe harbor, there was still a low risk of causing unintended changes in the genome. This suggests that GSH sites can be used to safely accommodate new therapeutic genes without posing a risk to patients.
“We introduced a fluorescent reporter gene into two new GSHs in primary human T cells obtained from blood. In addition, we inserted a fully functional LAMB3 gene, which is an extracellular protein in the skin, into the same GSHs in primary human dermal fibroblasts, and observed long-lasting activity,” as per Denitsa Milanova, Ph.D. “While these GSHs are uniquely positioned to improve on levels and persistence of gene expression in parent and daughter cells for therapeutics, I am particularly excited about emerging ‘gain-of-function’ cellular enhancements that could augment the normal function of cells and organs. The safety aspect is then of paramount importance.”
“An extensive sequencing analysis that we undertook in GSH-engineered primary human T cells clearly demonstrated that the insertion has minimal potential for causing tumor-promoting effects, which always is a main concern when genetically modifying cells for therapeutic use,” said Sai Reddy, ETH Zurich’s Department of Biosystems Science and Engineering. “The identification of multiple GSH sites also supports the potential to build more advanced cellular therapies that use multiple transgenes to program sophisticated cellular responses. This is especially relevant in T cell engineering for cancer immunotherapy.”
Collaboration to augment each other, not to compete in science
Collaboration has always been an imperative factor to many milestones in the history of science. “This collaborative interdisciplinary effort demonstrates the power of integrating computational approaches with genome engineering while maintaining a focus on clinical translation. The identification of GSHs in the human genome will greatly augment future developmental therapeutics efforts focused on engineering more effective and safer gene and cellular therapies,” said Wyss Founding Director Donald Ingber, M.D., Ph.D.
Even though this sort of research is not popular in all places, there have been many essential revelations since the Human Genome Project was initiated in 1990, intending to discover the DNA sequence of the entire human genome. The project was completed in 2003, and many of the findings were the inspiration to kick off more research like the work around genomic safe harbors with goals in mind to help cure diseases.
YouTube: Gene therapy explained by Professor Dave
YouTube: Bringing Gene Therapy to the Table | Dr. Jennifer Adair | TEDxNashvilleSalon
Photo credit: All pictures shown are symbolic. The feature image has been done by Cultura Allies. The photo in the body of the article was taken by Viacheslav Lakobchuk.
Editorial notice: Some parts of the quotes have been shortened and condensed for clarity. The information within has not been changed.