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A team of researchers at the Carl Gustav Carus Faculty of Medicine, TUD Dresden University of Technology, led by Prof. Frank Buchholz, has achieved a major breakthrough in genome editing technology. They’ve developed a cutting-edge method that combines the power of designer-recombinases with programmable DNA-binding domains to create precise and adaptable genome editing tools.

Traditional genome editing faced limitations in achieving ultimate precision until now. Prof. Buchholz’s team has broken through this barrier by creating what many have sought after: a zinc-finger conditioned recombinase. This innovative approach involves integrating a zinc-finger DNA-binding domain into specially designed recombinases. These enzymes remain inactive until the DNA-binding domain engages with its target site, adjacent to the recombinase binding area.

The significance of this achievement lies in the fusion of two key strengths: the targeting ease of programmable nucleases and the precise DNA editing capabilities of recombinases. This breakthrough overcomes existing limitations in genome editing techniques and holds vast promise for therapeutic gene editing and various biomedical applications.

Most approved gene therapies today, including those involving CRISPR-Cas9, work their magic on cells removed from the body, after which the edited cells are returned to the patient.

This technique is ideal for targeting blood cells and is currently the method employed in newly approved CRISPR gene therapies for blood diseases like sickle cell anemia, in which edited blood cells are reinfused in patients after their bone marrow has been destroyed by chemotherapy.

A new, precision-targeted delivery method for CRISPR-Cas9, published in the journal Nature Biotechnology, enables gene editing on very specific subsets of cells while still in the body—a step toward a programmable delivery method that would eliminate the need to obliterate patients’ bone marrow and immune system before giving them edited blood cells.

Some hereditary genetic defects cause an exaggerated immune response that can be fatal. Using the CRISPR-Cas9 gene-editing tool, such defects can be corrected, thus normalizing the immune response, as researchers led by Klaus Rajewsky from the Max Delbrück Center now report in Science Immunology.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disease of the immune system that usually occurs in infants and young children under the age of 18 months. The condition is severe and has a high mortality rate. It is caused by various gene mutations that prevent cytotoxic T cells from functioning normally. These are a group of immune cells that kill virus–infected cells or otherwise altered cells.

If a child with FHL contracts a virus—such as the Epstein-Barr virus (EBV), but also other viruses—the cytotoxic T cells cannot eliminate the infected cells. Instead, the immune response gets out of control. This leads to a cytokine storm and an excessive inflammatory reaction that affects the entire organism.

ERS Genomics discusses how gene editing is transforming the future of food.

A gene editing tool using a system known as CRISPR-Cas9 has recently been approved by the U.S. Food and Drug Administration (FDA) for sickle cell disease. The drug is known as Casgevy and the media has hailed this treatment as a ‘cure’ for sickle cell anemia patients. While it is still unclear if the drug completely cures these patients, clinical trials show exciting efficacy.

Sickle cell disease is a genetic blood disorder affecting thousands of US citizens. Many of these patients are African American and Hispanic. In sickle cell disease, hemoglobin, a protein in red blood cells that helps carry oxygen throughout the body, is mutated. As a result, blood cells change shape in the form of a sickle, giving the disease its name. Unfortunately, the mutated cells cause disruption of blood flow and prevent other blood cells from delivering oxygen to the body. This disease is extremely rare and can lower the quality of life in patients. Previously, there were limited treatments options including transfusions and medications for pain management. However, Casgevy provides a new option to help treat the patient and relieve pain for over a year after a single treatment.

One-time treatment using Casgevy improved life quality for sickle cell patients. A single-arm trial was conducted at multiple health centers in adults and adolescents. These patients were screened for two vaso-occlusive crises (VOCs) which are described as severely painful events due to a lack of oxygen delivery from sickle cell blood cells blocking blood flow. The primary measure of success in the trial was the number of VOCs after treatment. In total, 44 patients received Casgevy and 33 were able to follow up and be evaluated. Of the 33 patients that made it through the trial, 29 of them did not experience any VOCs for 12 months. This is a 93.5% success rate based on the number of patients that were analyzed. All 44 patients were able to successfully undergo treatment without any graft rejection. In addition, researchers concluded that this treatment was not only effective, but safe with few side effects.

Engineers at MIT, Penn State University, and Carnegie Mellon University have devised a way to manipulate cells in three dimensions using sound waves. These “acoustic tweezers” could make possible 3D printing of cell structures for tissue engineering and other applications, the researchers say.

Designing tissue implants that can be used to treat human disease requires precisely recreating the natural tissue architecture, but so far it has proven difficult to develop a single method that can achieve that while keeping cells viable and functional.

“The results presented in this paper provide a unique pathway to manipulate biological cells accurately and in three dimensions, without the need for any invasive contact, tagging, or biochemical labeling,” says Subra Suresh, president of Carnegie Mellon and former dean of engineering at MIT. “This approach could lead to new possibilities for research and applications in such areas as regenerative medicine, neuroscience, tissue engineering, biomanufacturing, and cancer metastasis.”

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Using CRISPR, an immune system bacteria use to protect themselves from viruses, scientists have harnessed the power to edit genetic information within cells. In fact, the first CRISPR-based therapeutic was recently approved by the FDA to treat sickle cell disease in December 2023. That therapy is based on a highly studied system known as the CRISPR-Cas9 genetic scissor.

However, a newer and unique platform with the potential to make large-sized DNA removals, called Type I CRISPR or CRISPR-Cas3, waits in the wings for potential therapeutic use.

A new study from Yan Zhang, Ph.D., Assistant Professor in the Department of Biological Chemistry at the University of Michigan Medical School, and her collaborators at Cornell University develops off-switches useful for improving the safety of the Type I-C/Cas3 gene editor. The study, “Exploiting Activation and Inactivation Mechanisms in Type I-C CRISPR-Cas3 for 3 Genome Editing Applications,” is published in the journal Molecular Cell.

Gene editing is revolutionizing the understanding of health and disease, providing researchers with vast opportunities to advance the development of novel treatment approaches. Traditionally, researchers used various methods to introduce double strand breaks (DSBs) into the genome, including transactivator-like effectors, meganucleases, and zinc finger nucleases. While useful, these techniques are limited in that they are time and labor intensive, less efficient, and can have unintended effects. In contrast, the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein-9 (Cas9) system (CRISPR/Cas9) is among the most sensitive and efficient methods for creating DNA DSBs, making it the leading gene editing technology.

CRISPR/Cas9 is a naturally occurring immune protective process that bacteria use to destroy foreign genetic material.¹ Researchers repurposed the CRISPR/Cas9 system for genetic engineering applications in mammalian cells, exploiting the molecular processes that introduce DSBs in specific sections of DNA, which are then repaired to turn certain genes on or off, or to correct genomic errors with extraordinary precision.^2,3 This technology’s applications are far reaching, from cell culture and animal models to translational research that focuses on correcting genetic mutations in diseases such as cancer, hemophilia, and sickle cell disease.⁴

Researchers exploit plasmids, the small, closed circular DNA strands native to bacteria, as delivery vehicles in CRISPR/Cas9 gene editing protocols. Plasmids shuttle the CRISPR/Cas9 gene editing components to target cells and can be manipulated to control gene editing activity, including targeting multiple genes at a time. Plasmids can also deliver gene repair instructions and machinery. For example, poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme that drives DNA repair and transcription.⁵ It is a critical aspect of CRISPR/Cas9 gene editing technology in part because it helps repair the DSBs created by the CRISPR/Cas9 system. PARP1 CRISPR plasmids can edit, knockout, or upregulate PARP1 gene expression depending on the specific instructions encoded in the plasmid.