Liver-targeted non-viral gene therapy gives hope to hemophiliacs
As a way of treating hemophilia, Japanese researchers have, for the first time, delivered gene therapy directly into the livers of baboons without using a viral carrier. The study’s results indicate that the method is safe and effective and may lead to a new way of treating the disease.
In recent years, gene therapy has been explored as a means of treating certain inherited diseases such as cystic fibrosis, hemophilia and sickle cell disease. The premise of gene therapy is simple: replace a faulty gene or add a new one in an attempt to cure disease or improve the ability of the body’s immune system to fight it.
In gene therapy, genetic material is delivered into the cells through carriers called vectors, typically viruses. Viruses are used because they can recognize and enter certain cells to deliver their genetic payload. But the major drawback to using viral vectors is that they can cause a severe immune response and can be toxic to cells. Using non-viral vectors lessens the risk of such a response.
In a preclinical trial, researchers from Niigata University in Japan have used hydrodynamic gene therapy, an alternative method of introducing genetic material, on baboons to test the safety and effectiveness of a potential treatment for hemophilia.
Hydrodynamic gene delivery involves rapidly injecting a large volume of DNA solution into the body. The speed and volume create pressure that forces the genetic material into the cells. Hydrodynamic gene therapy is thought to be simpler and more efficient than other gene delivery methods and has seen some success in delivering DNA, RNA, proteins and other synthetic compounds into the cells of small animals. In previous studies, the DNA solution was injected into the bloodstream, but the researchers used a more direct approach in the current study.
They injected the genetic material directly into a lobe of baboons’ livers. Under X-ray guidance, a computer-controlled injector injected the DNA solution into hepatic (liver) veins to target one of the four liver lobes. The solution contained a factor-IX-expressing plasmid, a small circular piece of DNA used to transport foreign DNA into cells.
A deficiency of the protein called factor IX (FIX), known as hemophilia B, impairs blood clotting. Hemophilia B is passed down from parents to children, but about one-third of cases result from a spontaneous genetic mutation. How much a person bleeds and how serious the bleed is depends on the amount of FIX in the blood plasma. The regular treatment following a bleeding episode is hospital admission and continuous intravenous infusions of concentrated FIX until the bleeding is controlled.
After examining the procedure’s effectiveness on blood clotting and plasma concentration of FIX, the researchers found that the baboons maintained therapeutic levels of FIX for 210 days. For gene therapy, the therapeutic level of the expressed FIX is usually considered 5% to 10% of the normal plasma level. Injection into the right and left medial lobes of the liver, particularly, sustained a therapeutic level above 30%. The researchers also found that reinjecting the baboons in the same liver lobe after 210 days brought FIX levels back to a therapeutic level.
Regarding the procedure’s safety, apart from a transient rise in liver enzymes immediately after injection of the DNA solution, the researchers saw no significant adverse reactions.
The researchers intend to continue testing their liver-lobe-specific hydrodynamic gene therapy on a larger group of animals to improve delivery safety and efficiency. Nonetheless, they say their novel treatment could provide a new mode of treatment for hemophiliacs and are keen to move on to clinical trials.
“Our results, although involving only five baboons, provide direct evidence in support [of] the notion that lobe-specific hydrodynamic gene delivery to [the] liver is applicable to humans, and clinical trials can be conducted,” the researchers said.
The study was published in the journal Molecular Therapy: Nucleic Acids.
Source: Niigata University