A potentially game-changing DNA repair kit has been used to correct genetic mutations that cause hereditary kidney disease in children and young adults.
This new study describes the international team’s development of a DNA repair vehicle to genetically correct faulty podocin—a common genetic cause of inheritable Steroid Resistant Nephrotic Syndrome (SRNS).
A debilitating hereditary kidney disease affecting children and young adults has been genetically corrected with the help of a potentially game-changing DNA repair kit.
An international team developed a DNA repair vehicle to genetically correct faulty podocin, a common genetic cause of inheritable Steroid Resistant Nephrotic Syndrome (SRNS), in this new study.
Human viruses are commonly used in gene therapy applications to perform genetic repairs. These are used as “Trojan Horses” to enter the cells containing the errors. The most common systems are lentivirus (LV), adenovirus (AV), and adeno-associated virus (AAV), which are all relatively harmless viruses that easily infect humans. The common limitation of all of these viruses is that their viral shells confine them in space. This restricts the amount of cargo they can transport, specifically the DNA kit required for effective genetic repair, severely limiting their utility in gene therapy.
The team, led by Dr. Francesco Aulicino and Professor Imre Berger from Bristol’s School of Biochemistry, used synthetic biology techniques to re-engineer baculovirus so that it is no longer limited by a small cargo capacity. Baculovirus is an insect virus that is not harmful to humans.
This modified baculovirus is thought to be safe because it can only replicate in insect cells and not in human cells. The scientists then delivered much larger DNA pieces than had previously been possible using their engineered baculovirus and incorporated these into the genomes of a wide range of human cells.
The team used podocytes derived from patients who carried the disease-causing genetic error to demonstrate the efficacy of their technology. By developing a DNA repair kit comprised of protein-based scissors and the nucleic acid molecules that guide them—as well as the DNA sequences to replace the faulty gene—the team delivered a healthy copy of the podocin gene as well as the CRISPR/Cas machinery to insert it with base-pair precision into the genome using a single engineered baculovirus. Podocin was able to resurface on the cell surface, reversing the disease-causing phenotype.