New prime editing approach could potentially treat multiple genetic diseases

A new multipurpose genome editing approach could address around a third of rare genetic diseases.

The approach, called PERT, targets nonsense mutations – genetic errors that cause cells to stop protein synthesis prematurely. These mutations account for approximately 30 percent of rare diseases and 24 percent of all disease-causing mutations. PERT equips cells with molecular machinery to bypass premature stop signals, allowing production of full-length, functional proteins regardless of which gene harbours the mutation.

'We're excited by the possibility that you could develop a single editing agent into a drug that may help many different types of patients, circumventing the need to invest multiple years and millions of dollars to develop each new genetic medicine for each individual,' said Professor David Liu, the genome editing pioneer who led the research at the Broad Institute of MIT and Harvard in Massachusetts.

Publishing their developments in Nature, the team used prime editing – a DNA-editing method that enables precision genome editing without double-stranded breaks – developed by Professor Liu's laboratory in 2019 (see BioNews 1021, 1243 and 1285) – to permanently install an engineered suppressor transfer RNA (tRNA) into cells' genomes. This small RNA molecule instructs the protein-making machinery to insert an amino acid where it would normally halt at a premature stop signal. After screening tens of thousands of tRNA variants, researchers identified a highly efficient version and inserted it by replacing an existing redundant tRNA that cells do not need.

With this approach, researchers have restored protein production in human cell models of Batten disease, Tay-Sachs disease, Niemann-Pick disease type C1, and cystic fibrosis. In each case, enzyme activity recovered between 20 and 70 percent of normal protein levels – theoretically sufficient to alleviate disease symptoms. The team also tested PERT in mice modelling Hurler syndrome, a lysosomal storage disorder. Despite restoring only about seven percent of normal enzyme activity in affected tissues, this was sufficient to nearly eliminate all disease signs.

Importantly, the approach produced no detectable off-target genetic changes nor interfered with cells' production of other proteins. This may be because mammalian cells have several backup systems for supporting proper protein synthesis, and PERT results in only modest levels of the engineered suppressor tRNA.

The team are hopeful that PERT has the potential to treat many rare diseases caused by nonsense mutations, including Duchenne muscular dystrophy, phenylketonuria, and Stargardt disease.

However, several hurdles remain before PERT can reach patients. The biggest challenge is delivery – getting the editing machinery into all cells needing correction, particularly in organs like the brain or lungs. Previous gene therapies have used deactivated viruses or lipid-based delivery systems, but each approach has limitations.

'It has tremendous tangible potential for scalability and for going away from bespoke, customised, personalised medicine to more generally applicable types of therapeutics,' Professor Rodolphe Barrangou from North Carolina State University, who was not involved in the research, told the New York Times. However, he continued: 'I don't want to discount the longevity of the process and the many different difficulties inherent to delivery and regulation and clinical testing and de-risking and eventually approval'.

The team is now optimising PERT and testing it in additional animal models.