New gene therapy uses blood cells to deliver key Friedreich’s ataxia protein
Study: Treatment delayed signs and symptoms of disease in mouse model
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Researchers have developed a new gene therapy for Friedreich’s ataxia (FA) that uses blood cells as delivery vehicles to transport a functional version of the frataxin protein to cells throughout the body, according to a study.
In a new study, the scientists demonstrated that their therapy doesn’t disrupt the function of human blood stem cells and that the treatment delays signs and symptoms of disease in a mouse model of FA. The team said their results “support a cell and gene therapy strategy for long-term stabilization of [FA],” though they noted that more preclinical work is needed before this approach can be tried in people.
The study, “Therapeutic activity of a hematopoietic stem cell-delivered cell-penetrating frataxin in Friedreich’s ataxia models,” was published in Cell Reports Medicine.
Scientists took different approach to delivering protein
FA is caused by mutations in the gene that encodes frataxin, a protein that’s vital for the function of energy-making cellular structures called mitochondria. The lack of functional frataxin disrupts energy production in cells throughout the body, ultimately driving disease symptoms.
Several experimental FA therapies in development seek to deliver a functional version of the frataxin protein, or the gene encoding the protein, to cells in the body. But this therapeutic approach has a major obstacle: FA affects cells throughout the body, and it’s often not possible to deliver a protein or gene to every single one of the body’s cells. In particular, the central nervous system is affected by FA, but the blood-brain barrier represents a key obstacle to getting therapies into the brain and spinal cord.
In this study, a team led by scientists in the U.K. set out to deliver functional frataxin using a different approach. Instead of trying to deliver the protein or its gene to all the body’s cells at once, the new gene therapy specifically aims to modify hematopoietic stem and progenitor cells (HSPCs), which are specialized cells that live in the bone marrow and are responsible for making new blood and immune cells.
The new therapy uses a viral vector to deliver to HSPCs a gene encoding a version of the frataxin protein that has two key biochemical modifications. First, the protein contains a signaling sequence that allows it to be secreted by blood and immune cells. And second, another signaling sequence allows the protein to be taken up by other types of cells in the body.
The basic idea is that the modified HSPCs will make new blood cells carrying the modified protein, and these blood cells will then travel throughout the body like delivery drivers, secreting the protein so it can be taken up by other cells. Importantly, since immune cells such as macrophages can travel into the brain, this strategy should allow the therapeutic protein to be delivered to all the cells that are hardest hit in FA.
Treated mice showed less damage in brain regions affected by FA
In the new study, the researchers first tested their new therapy in human HSPCs to make sure that the modified cells would still be able to grow into new blood and immune cells. Findings suggested that the treated HSPCs had no problems making new cells and that those cells produced the modified frataxin protein.
The researchers then tested their therapy in a mouse model of FA. Results showed that the treatment delayed the start of movement problems in the mice. The treated mice also showed less damage in brain regions affected by FA, including larger nerve cells compared with untreated FA animals and enhanced function of a key mitochondrial enzyme. The modified frataxin protein was detectable in the mice’s blood, which suggests that blood cells are secreting the protein as designed.
“Transplantation of modified HSPCs produced stable [frataxin] secretion in the bloodstream and delayed the onset of motor coordination symptoms, accompanied by improved biochemical and anatomical parameters,” the researchers wrote.
The scientists stressed that their study was limited to just one mouse model of FA. Further research into the safety and effectiveness of this approach in other preclinical models will be necessary before this treatment strategy can be tested in people.
