A life-threatening kidney disease may be one day be a treatable condition thanks to work by researchers at Newcastle University, and patients with the illness - Joubert syndrome. For the first time, the scientists were able to use gene editing to repair the genetic error one of the causative genes, called CEP290, in a mouse model and patient-derived cells grown in the lab. The study, which opens up the possibility of personalized therapeutics for the disease, was reported in the Proceedings of the National Academy of Sciences (PNAS).
Joubert syndrome is a rare condition, impacting only one in 80,000 births. It affects brain development and causes a range of mental and physical problems. The kidneys of one-third of patients will eventually fail. The disease is considered a ciliopathy - the genetic mutations that underlie it disrupt a cellular structure called the cilium or its basal bodies.
Many genetic mutations have been linked to Joubert syndrome, some of which are in CEP290. In patients with disease-causing CEP290 mutations, the resulting kidney problems often require dialysis or transplant. Researchers have learned that it’s possible to use an oligonucleotide (a chain of nucleic acids) to induce the cell's natural editing machinery to splice out the mutated CEP290 exon.
"This is the first time that gene editing within the kidney has been performed, even in a mouse model, as the design and delivery of the gene editing to the kidney has previously been thought to be too difficult,” said the research leader, Professor John Sayer, from the Institute of Genetic Medicine, Newcastle University.
"Our research is a major step [forward] as we now know how we may be able to offer a therapy that corrects the gene mistake within kidney cells and prevent the development of genetic kidney disease. This work paves the way for personalized genetic therapies in patients with the inherited kidney disease."
For this study, the researchers used a mouse model as well as kidney cells that were donated by patients with Joubert syndrome. From urine samples, the scientists could grow kidney cells in the lab to assess the effects of gene-editing on the cells. They confirmed that the gene edit worked in rodents with kidney cysts and a mouse model of Joubert syndrome.
"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. We have shown that the kidney disease in a mouse can be dramatically improved using this exon-skipping gene editing technology,” explained Professor Sayer, a Consultant Nephrologist at Newcastle Hospitals NHS Foundation Trust.
"This will mean that we can edit out genetic mistakes that are leading to inherited kidney diseases such as Joubert syndrome and we are testing this technology in other mouse models before we move into patient studies. We expect that we will start to test treatment of patients with exon-skipping within the next three years." Researchers are now collaborating with a drug company to take the new technology into the clinic.
Asher Ahmed is a teenager with Joubert syndrome that was instrumental in the study of the disease. He has provided many samples over the years, including ones that Newcastle researchers used to develop cell lines. It’s likely that he will need a kidney transplant one day, and he suffers from a range of medical problems. His kidneys are damaged, he has problems with vision, coordination, communication, and balance, and takes several drugs to stay well.
"It is very important that research is done into Joubert syndrome and the linked kidney damage as this will hopefully prevent patients in the future needing a kidney transplant,” said Asher's mother, Nabila Ahmed. She is hopeful that efforts like this study will improve the quality of life for patients in the future.
"All throughout Asher's life, he has lived with the effects of Joubert syndrome, and five years ago he was diagnosed with kidney disease as he has the CEP290 gene,” she added. “Asher is on a number of tablets to keep him well and this is an added complication to an already difficult condition. We know he will likely need a transplant in the future and this is a worry. We were happy for Asher to provide samples for the study as anything that helps further understanding into the condition is well worth doing, so it's great to see the study's positive results."
Learn more about ciliopathies from the video above, and hear more about Joubert syndrome from the following video.