Gene therapy shows early promise for fatal childhood liver disease
Treatment safely restored liver function in mouse study of ARC syndrome
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Scientists in the U.K. have created a liver-specific gene therapy that could potentially treat arthrogryposis renal dysfunction cholestasis (ARC) syndrome, a fatal childhood disease marked by cholestasis, or slowed flow of the digestive fluid bile, according to new lab research.
The gene therapy was found to safely restore liver function and improve survival in a mouse model of ARC syndrome. In fact, data showed that more than twice as many mice receiving the gene therapy survived compared with those given an inactive control.
Further, an increase in gene correction was observed in the treated animals over time, the researchers noted.
“Our findings are important because it provides proof-of-concept that gene therapy could become a realistic treatment for ARC syndrome,” Claudiu Cozmescu, PhD, the study’s first author at University College London (UCL), said in a university news story detailing the research.
Cozmescu stressed that, “before human trials, further long-term toxicology and safety studies will be needed.” But the scientists noted that their work “demonstrates that liver-directed gene therapy can be both safe and effective in treating cholestatic liver disorders such as ARC syndrome.”
The study, “Safety and efficacy analysis of in vivo lentiviral gene therapy in pre-clinical ARC syndrome models,” was published in the journal Nature Communications.
ARC syndrome is a rare genetic disease characterized by kidney dysfunction and cholestasis, or the slowing or stalling of bile flow from the liver to the small intestine. It’s also marked by joint contractures, in which shortening and stiffening of the surrounding tissues limit a person’s range of motion.
About three-quarters of cases are caused by mutations in the VPS33B gene and are known as ARC type 2, with the remainder due to defects in a related gene called VIPAS39; these cases are known as ARC type 1.
The two genes normally work together to form a protein complex that helps direct other proteins to the correct location inside liver cells. When this system fails, proteins normally located on the bile canaliculi, the tiny channels between liver cells that carry bile, end up in the wrong place. This leads to cholestasis, causing symptoms such as jaundice, a yellowing of the skin and whites of the eyes, as well as progressive liver damage that typically advances to scarring and liver failure.
While most infants with ARC syndrome don’t survive past their first year of life, some of those with ARC type 1 and milder disease can survive into childhood.
UK researchers say design of gene therapy ‘is critical’
Now, a team led by UCL researchers designed a gene therapy that uses a harmless, modified lentiviral virus to deliver a working version of the VPS33B gene to cells. The researchers developed two viruses: one that targets all cell types and another specific to liver cells.
In lab-grown human liver cells lacking the VPS33B gene, both approaches restored VPS33B protein production and helped the cells to form normal bile canaliculi-like structures.
Because lentiviral gene therapy has raised concerns about possible cancer risk, the team ran a nine-month safety study involving mice carrying one working and one faulty copy of the VPS33B gene.
Liver tumors developed in 50% of mice given the general-purpose virus and its inactive control (not delivering the VPS33B gene), indicating an increased the risk of cancer. In contrast, no liver abnormalities were observed in mice that received the liver-specific virus or its inactive control, the researchers noted.
These findings highlight “how a gene therapy is designed is critical: targeting treatment specifically to the liver improved safety while maintaining benefit,” Cozmescu said.
Still, the general-purpose approach was not associated with tumors when given to healthy mice with two working VPS33B copies, the data showed.
According to the researchers, because the VPS33B protein is thought to protect against liver tumor development, these results “support a two-hit model … where reduced VPS33B [levels] acts as a predisposing event requiring additional secondary alterations.” Such alterations could potentially involve VPS33B gene integration and resulting gene activity changes to cause tumor formation, the team wrote.
Liver-specific gene therapy approach helped mice live longer
Next, the researchers tested whether the liver-specific approach could treat ARC syndrome in a mouse model lacking both copies of the VPS33B gene in the liver. To make the disease symptoms more severe and easier to measure, the mice were fed a liver stress-inducing diet.
During one month on this diet, 80% of mice receiving the liver-specific gene therapy survived, compared with 33% in the group given the inactive control. Treated mice also gained about four times more weight than untreated mice in the first week, the data showed.
Blood levels of alkaline phosphatase, a liver damage marker, were about four times lower in treated mice after one month, and about 10 times lower by the end of the study. The therapy was also associated with additional signs of improved bile flow, the researchers noted.
At the microscopic level, treated livers had noticeably less scarring than untreated livers, and the treatment restored much of the branching network structure of the bile canaliculi, according to the researchers.
Additional experiments showed that the level of gene correction achieved increased gradually, eventually reaching about 110 times the level normally seen in healthy mice, “suggesting a possible effect of the competitive advantage of corrected cells repopulating the liver,” the team wrote.
Paul Gissen, PhD, the study’s senior author and a clinical professor at UCL Great Ormond Street Institute of Child Health, said the results to date are promising.
“The final version of the treatment is shown to be safe so far,” Gissen said. “The earlier version gave us a new window into the understanding of how to make gene therapies safer for … patients. One of these insights is to keep the levels of genes as close to those found in healthy cells as possible.”
According to Cozmescu, “the findings should be of interest to patients and families affected by rare liver diseases, clinicians, gene therapy researchers, biotech developers, regulators, and charities supporting rare disease research.”
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