Muscle mass with nanoparticle-based anti-inflammatory therapy


The images at the top show representative muscle histology with a larger area of ​​muscle fiber (pink) and improved morphology (less damaged fibers, whitespace) two weeks after mice with DMD were treated with a single dose of IL-4 NPs (PA4), compared with negative PBS control. Stair bar, 300um. The images at the bottom show a heat map of a flow cytometry analysis (left) with the location of the positive T cells for the CD3 marker indicated with a red arrow and how to inject IL-4 NPs (PA4) increased the recruitment of T cells to muscles. Credit: Wyss Institute at Harvard University

Muscular dystrophies are a group of genetic diseases that lead to the progressive loss of muscle mass and function in patients, with especially severe incurable Duchenne muscular dystrophy (DMD), which affects all the muscles of the body, mainly in children. DMD can be caused by more than 7,000 unique mutations in the largest gene in the human genome, which encodes a central protein in muscle fibers. Although this staggering number of mutations variably blocks muscle function, affected muscles share another common feature: chronic inflammation.

How contributes significantly to the speed and severity of degeneration, researchers are following different anti-inflammatory approaches that could be applied to the weakened muscles of patients with DMD. To date, it has become clear that broad systemically applied anti-inflammatory therapies cannot achieve sufficient efficacy in individual muscles and that, in addition, they can be toxic to patients and increase the risk of infections. To overcome these barriers, local action therapies that could be applied in situ to the affected muscles would have significant advantages.

Now, a research team from the Harvard Institute of Biological Inspiration Biological Engineering and the John A. Paulson School of Engineering and Applied Sciences (SEAS), led by David Mooney, Ph.D., a member of the Fundamental Faculty of the Wyss Institute, has developed a new approach in which specifically designed anti-inflammatory nanoparticles (PNs) that could be applied locally and selectively to chronically inflamed muscles severely affected or at more immediate risk of deterioration, and perhaps difficult to achieve with oral therapists. In an advanced model of mouse DMD, this strategy increased the volume of muscles covered by myofibers and improved muscle functions by increasing the number of infiltrating anti-inflammatory regulatory T cells (Tregs). The findings are published in Scientific advances.

A solution based on biomaterials: design and validation

“By delivering NP-based cytokines, we can create a therapeutic immune state in DMD-affected muscles that targets inflammation as a universal engine of the disease,” said Mooney, who runs the Immuno-Materials platform. from the Wyss Institute and is also Robert P Professor of Bioengineering in the Pinkas family at SEAS. “Given the highly effective localized delivery of the cytokine interleukin-4 (IL-4), this approach could be developed as a stand-alone therapy or, in the future, used in combination with genetic approaches designed to repair specific DMD mutations in patients. “

It is believed that proinflammatory and anti-inflammatory immune cells recruited to waste muscles and differentiate them further play an active game of tug-of-war. Both can temporarily gain superior strength with muscles going through continuous cycles of injury and myofiber regeneration, while in the longer term the injury always gains. It is important to note that the identities and activities of immune cells are controlled by pro and anti-inflammatory cytokines, immune modulating molecules that are released by immune cells or other muscle tissues.

In 2018, Mooney’s team had shown that gold nanoparticles (PN) that exhibited the anti-inflammatory cytokine interleukin-4 (IL-4) when injected locally into injured mouse mice, could improve muscle strength a 40% compared to PN control. The NPs were designed so that a gold NP was partially coated with a layer of biocompatible polymer polyethylene glycol (PEG). In parts of the NP surface revealed by coating voids, IL-4 cytokine molecules bound (chemically conjugated), allowing them to be protected by the surrounding PEG and remain bioactive for extended periods of time after injection into the muscle tissue. and uptake by muscle immune cells.

To study the effects of IL-4-carrying NPs and IL-10-carrying NPs (a different-acting anti-inflammatory cytokine) on DMD-affected muscles, the researchers used an existing mouse model, known as in Mdx, which carries a DMD Mutation found in human patients. Because muscle degeneration occurs much more slowly in Mdx mice than in human patients, they developed a micro-injury approach in which the muscles in the hind limbs of aged Mdx mice were repeatedly injured to accelerate the progression of murine disease and to imitate more closely the human disease. In Mdx mice, the micro lesion caused chronic inflammation similar to DMD and damage that persisted for several weeks.

Invigorating muscles with T cell action.

One week after the end of the micro-injury procedure, they injected IL-4 NPs (and IL-10 NPs) directly into the chronically injured muscle and after two more weeks analyzed the effects. “Cytokine therapy with IL-4 but not IL-10 conjugated to NP significantly increased the area in cross-sections covered by , and in live animals, the treated muscles showed a fourfold increase in contraction force and speed (speed) compared to the mice in the control groups, ”said first author Theresa Raimondo, Ph.D. , who did the work as a graduate student in Mooney’s group and is now a postdoctoral fellow at MIT.

DMD is life-threatening when it affects the diaphragm and heart muscles. The team hopes its strategy will one day help improve breathing and heart function in patients, although future studies will need to evaluate that possibility.

“Interestingly, we could contribute regenerative effects to a specific increase in Tregs, a type of immunosuppressive T cell that was known to counteract inflammatory processes in muscles weakened by DMD.”

The team observed a 50% increase in the number of Tregs in chronically injured muscles in aged Mdx mice, while the number of other types of immune cells, including neutrophils, dendritic cells, cells Natural killer cells, monocytes and macrophages, remained unchanged with their cytokine-based therapy.

In particular, macrophages, in their anti-inflammatory state called M2, had also been suggested to contribute to the restoration of muscle strength and function in mouse DMD models, and Mooney’s team previously found that it was key. to repair acutely injured muscles in normal mice. However, in the chronically inflamed muscles of the advanced Mdx model that were targeted with NP-based IL-4 therapy in the new study, M2 macrophages did not contribute significantly to the therapeutic effect. “Our combined results highlight that the same cytokine therapy can achieve very different immune outcomes with therapeutic effects on muscles depending on the type of inflammation that exists,” Mooney said.

“This approach developed by Dave Mooney’s group at the Wyss Immuno-Material Initiative could be developed as a strategically applied alternative solution for the treatment of patients with Duchenne muscular dystrophy loss of muscle mass and function cannot be effectively stopped by any The same basic principle of NP-based cytokine therapy could also have potential for a variety of other muscle disorders in which inflammation is a major force, “said Wyss founding director Donald Ingber. , MD, Ph.D., who is also the vascular professor of Judah Folkman. Biology at Harvard Medical School and Boston Children’s Hospital, and professor of bioengineering at SEAS.

A golden ticket for faster muscle recovery

More information:
Theresa M. Raimondo et al, Anti-inflammatory nanoparticles significantly improve muscle function in a murine model of advanced muscular dystrophy, Scientific advances (2021). DOI: 10.1126 / sciadv.abh3693

Citation: Muscle with nanoparticle-based anti-inflammatory therapy (2021, June 24) retrieved June 24, 2021 from

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