Joubert syndrome, an inherited brain disorder that affects one in 80,000 newborns, causes kidney failure in about a third of patients, many of whom end up requiring a transplant or dialysis. This inherited form of kidney disease is caused by a mutation in the gene CEP290, and now scientists in the U.K. say they have early proof that a form of gene editing called “exon skipping” can correct the error.
Researchers at Newcastle University used a synthetic strand of DNA to trick cells into bypassing the damaging CEP290 mutation, they reported in the Proceedings of the National Academy of Sciences. They used kidney cells from a 19-year-old patient with Joubert syndrome for their early testing of the technique.
They went on to try exon skipping in a mouse model of Joubert syndrome, as well as rodents with kidney cysts and kidney failure. The technique halted kidney disease in those models, they reported.
“The treatment of genetic kidney disease is challenging, as this requires both the correction of the underlying gene defect and the delivery of the treatment,” said John Sayer, Ph.D., a consultant nephrologist at Newcastle Hospitals NHS Foundation Trust, in a statement. “This work paves the way towards [personalized] genetic therapies in patients with the inherited kidney disease.”
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Exon skipping has primarily drawn attention in Duchenne muscular dystrophy (DMD). It is the basis of Sarepta’s FDA-approved treatment Exondys 51, which is aimed at a subset of patients with a form of the disease that response to exon 51 skipping. The technology has run into some development difficulties, however. Earlier this year, Daiichi Sankyo released data on its exon-45-skipping DMD drug DS-5141b that raised efficacy questions. That drug is in a developing class known as antisense oligonucleotides.
Several research groups are now examining the emerging gene-editing system CRISPR-Cas9 in the treatment of DMD. They include scientists at Exonics, a startup that’s using an RNA guide molecule to deliver CRISPR into cells and skip 4 exons, which they believe will help 35% of patients with DMD. Ultimately they say their CRISPR method will be able to reach 80% of patients.
Sayer’s team at Newcastle is now looking for a drug company to help them formulate their exon-skipping technology into a compound that can be tested in patients with Joubert syndrome. They are planning to start human trials within three years, they reported.