In a new study, a sponge-like implant in mice helped to guide a treatment that slowed or stopped a degenerative condition similar to multiple sclerosis (MS) in humans. It also gave researchers a first look at how primary progressive MS, the fastest-progressing version of the disease, attacks the central nervous system early on.
If administered early, the nanoparticle-based treatment prevented mice from developing symptoms such as paralysis. If given after the first symptoms emerged, it reduced symptom scores by half compared to untreated mice.
In MS, researchers know that immune cells attack the myelin sheath around nerves, but it’s hard to discover the details of how that is happening. Because the attacks occur in the brain and spinal cord, it’s not possible to take biopsies from living patients.
“Right now, we simply can’t get access to diseased tissue from MS patients in any regular way. Some patients donate brains after death, but at that point the disease has progressed quite far,” said Aaron Morris, University of Michigan assistant professor of biomedical engineering and co-corresponding author of the study in the Proceedings of the National Academy of Sciences.
Without an understanding of how the disease works, researchers have been unable to develop effective treatments. Currently, the only FDA-approved drug helps slow disease progression but does not offer full remission. Since it works by damping down the immune system, it also exposes patients to infection.
To help enable better treatments, the research team used a sponge-like implant, previously used to diagnose relapsing MS or discover whether an implanted organ is being rejected. Also known as a scaffold, it is a cylinder of biodegradable polyester, 13 millimetres diameter and 2 millimetres in height, full of small pores where cells can attach.
After implanting the scaffold just under the skin around the shoulder blades, the team induced the MS-like autoimmune condition in half of the mice while the other half served as a healthy comparison. Over several weeks, immune cells attracted to the foreign object grew into the pores, along with other cells. This created an easily biopsied tissue surrogate outside of the central nervous system that provides clues to the disordered immune response in MS.
The team analysed the tissue from the sponges with single-cell RNA sequencing to discover what individual cells were doing, which helped unravel differences between diseased and healthy tissue. A group of proteins called CC chemokines were particularly overactive in diseased tissue. These proteins call over other cells to fight infection, but when the call is too loud, they trigger the immune cells to attack healthy tissue.
With this information in hand, the researchers developed injectable nanoparticles, just 400 nanometres in diameter, that surround a key CC chemokine and disrupt the misplaced inflammation. This mechanism prevented symptoms from developing when the mice were treated early and reduced their symptoms by more than half if given after onset. A close look at immune cells confirmed less disease activity in nanoparticle-treated mice.
“The scaffold provides an unprecedented ability to track disease dynamics and to investigate the underlying mechanisms, particularly at early stages. Therapies targeting these early mechanisms can halt disease progression before significant tissue damage,” said Lonnie Shea, the Steven A. Goldstein Collegiate Professor of Biomedical Engineering and co-corresponding author of the study.
