New DNA repair-kit successfully fixes hereditary disease in patient-derived cells: New technology that can rewrite the genetic code raises hopes for gene therapy

Genetic mutations which cause a debilitating hereditary kidney disease affecting children and young adults have been fixed in patient-derived kidney cellsusing a potentially game-changing DNA repair-kit. The advance, developed by University of Bristol scientists, is published in Nucleic Acids Research.

In this new study, the international team describe how they created a DNA repair vehicle to genetically fix faulty podocin, a common genetic cause of inheritable Steroid Resistant Nephrotic Syndrome (SRNS).*

Podocin is a protein normally located on the surface of specialised kidney cells and is essential for kidney function. Faulty podocin, however, remains stuck inside the cell and never makes it to the surface, terminally damaging the podocytes. Since the disease cannot be cured with medications, gene therapy which repairs the genetic mutations causing the faulty podocin offers hope for patients.

Typically, human viruses have been utilised in gene therapy applications to carry out genetic repairs. These are used as a ‘Trojan Horse’ to enter cells carrying the errors. Currently dominating systems include lentivirus (LV), adenovirus (AV) and adeno-associated virus (AAV), which are all relatively harmless viruses that readily infect humans. However, these viruses all share the same limitation in that they are restricted in space within their viral shells. This in turn constrains the amount of cargo they can deliver, namely the DNA kit required for efficient genetic repair, which significantly limits the scope of their application in gene therapy.

By applying synthetic biology techniques, the team led by Dr Francesco Aulicino and Professor Imre Berger from Bristol’s School of Biochemistry, re-engineered baculovirus, a for humans harmless insect virus which is no longer constrained by limited cargo capacity.

“What sets apart baculovirus from LV, AV, and AAV is the lack of a rigid shell encapsulating the cargo space.” said Dr Francesco Aulicino, who led the study. The shell of baculovirus resembles a hollow stick — it simply becomes longer when the cargo increases. This means a lot more sophisticated tool-kit to repair a genetic defect can be delivered by the baculovirus, making it much more versatile than commonly-used systems.

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