image: Infographic: First Step Towards Gene Therapy for Multiple Sclerosis
Credit: Netherlands Institute for Neuroscience
In gene therapy, a gene (a piece of DNA) is introduced into cells. This process uses a virus that has been stripped of its disease-causing properties—referred to as a viral vector—as the delivery method. With the help of the inserted DNA, these cells can produce proteins that can function as medicine. In this way, the brain cells themselves become producers of the treatment. This therapeutic strategy shows great promise for the treatment of neurological disorders. Researchers at the Netherlands Institute for Neuroscience have now taken an important step toward making this possible for treating MS.
Viral Vectors as Delivery Vehicles
In MS, inflammation develops in the brain and spinal cord. This damages a protective layer of fat surrounding nerve cells, also known as myelin. Whereas gene therapy normally means getting the viral vector to the area in need of treatment by administering injections into the brain, this is not feasible in MS. This is because the inflammatory areas arise at unpredictable sites in the nervous system.
The research team therefore used a viral vector with a specially engineered protein capsule as a transport vehicle. Thanks to this special capsule, the viral vector can cross the blood-brain barrier and reach the brain after a simple injection into the bloodstream. "This means we no longer need to inject directly into the brain," says Paul Nijhuis, lead author of the study. "The major advantage is that we avoid complex neurosurgical procedures to deliver the therapeutic gene to its target."
Cell-Type-Specific Expression
When gene therapy is administered via the bloodstream, it is important that the therapeutic protein is produced only in the organ to be treated and in the right cells to avoid unwanted side effects. This study therefore investigated viral vectors containing specific “promoters”. Promoters are pieces of DNA that act as gene switches, thereby determining in which cells a gene is switched on or off.
The researchers introduced viral vectors with different promoters into mice and analysed in which cells and organs gene expression could be detected. Most promoters had strong specificity for the targeted cell types in the nervous system, and virtually no expression outside the nervous system. Nijhuis explains, ‘If you can selectively activate a gene therapy in certain cell types, the treatment becomes specific to that cell.’
Maintained Function During Inflammation
The researchers went one step further by testing whether the promoters also continue to work cell-specifically in an inflamed brain, as occurs in MS. For this, they used a mouse model mimicking MS. Also in this model, the promoters remained active in the targeted cell types, even within the inflammatory areas. This is an important finding because it is precisely these inflamed areas that are targeted for gene therapy. ‘For MS, myelin-forming cells are very important for recovery and we managed to reach precisely these cells with our minimally-invasive gene therapy,’ Nijhuis explains.
Future Research
Using the unique collection of brain tissue from MS patients from the Netherlands Brain Bank (NHB), recently published research has identified possible genes suitable for gene therapy. Inge Huitinga, neuroimmunologist and director of the NHB, outlines the follow-up steps already underway: ‘We are now investigating the therapeutic effects of these genes with the gene therapy method developed by Paul Nijhuis, first in the animal model, but in the future, we hope this can also provide insight into a regenerative therapy to treat targeted inflammation in people with MS.’ Joost Smolders, neurologist at Erasmus MC Rotterdam, added: "MS treatments now mainly focus on preventing or inhibiting inflammation. The main aim is to prevent an increase in disability. If the current research leads to new treatments that can repair tissue damaged by MS, that could be very meaningful in allowing people with MS to improve in neurological functioning."
Source: Molecular Therapy Methods
Expert contact
Paul Nijhuis: p.nijhuis@nin.knaw.nl
Joost Verhaagen: j.verhaagen@nin.knaw.nl
Media contact
Communications department: communicatie@nin.knaw.nl
About the Netherlands Institute for Neuroscience
At the Netherlands Institute for Neuroscience, research is conducted on neural circuits and their role in mental functions. Innovative basic science is closely integrated with state-of-the-art translational research on malfunctioning circuits in brain diseases. The gene therapy research for MS is a collaboration between the Neuroregeneration research group (led by Joost Verhaagen) and the Neuroimmunology group (led by Inge Huitinga).
About the Start2Cure Foundation
The Start2Cure Foundation co-funded this research. The foundation aims to improve the quality of life for people with progressive multiple sclerosis in the short term and to bring a cure closer in the long term. It provides funding for both medical scientific research and social initiatives. Learn more about the Start2Cure Foundation through the following links:
About Health-Holland
This research was made possible by support form Health-Holland, Top Sector Life Sciences & Health. https://www.health-holland.com