28 June 2021

No inflammation – no dystrophy

Muscular dystrophy is a group of genetic diseases that lead to progressive loss of muscle mass and motor function in patients. Duchenne muscular dystrophy is especially severe, which mainly affects boys in early childhood. The causes of the disease can be more than 7000 different mutations in the largest gene of the human genome, which encodes the cytoskeletal protein dystrophin, which provides strength, stability and functionality of muscle fibers. Regardless of the mutation underlying Duchenne dystrophy, the affected muscles have one thing in common – chronic inflammation.

Since chronic inflammation correlates with the rate and severity of muscle degeneration, researchers are developing various anti-inflammatory therapy approaches for treatment. To date, there is sufficient evidence that widely used systemic anti-inflammatory treatments cannot be sufficiently effective in individual muscles. In addition, they can be toxic to patients and increase the risk of infections. Therefore, local treatment that can be directed at the affected muscles will have significant benefits.

Professor David Mooney of the Wyss Institute at Harvard University and his colleagues have developed a new approach using specially created anti-inflammatory nanoparticles that can be applied locally and selectively to chronically inflamed, severely affected or at risk of muscle damage. In mouse models of Duchenne muscular dystrophy, this strategy led to an increase in muscle volume and improved motor functions by attracting anti-inflammatory regulatory T cells.

Biomaterial-based solution

Researchers have suggested that the delivery of anti-inflammatory cytokines using gold nanoparticles to muscles affected by Duchenne muscular dystrophy will suppress inflammation as the main pathogenetic mechanism of the disease. Interleukin-4 (IL-4) was selected for localized delivery.

It is known that pro-inflammatory and anti-inflammatory immune cells, being in balance, maintain the normal functioning of muscle fibers, which constantly alternate cycles of damage and regeneration.

In the long run, damage always prevails. It is important to note that the activity of immune cells is controlled by pro- and anti–inflammatory cytokines - immunomodulatory molecules that are released in muscle tissue.

In 2018, the Muni group showed that gold nanoparticles carrying the anti-inflammatory cytokine IL-4, when injected locally into acutely damaged muscles of mice, restored muscle strength by 40% more effectively than "empty" nanoparticles. The gold nanoparticles were constructed in a special way: the gold core was partially covered with a layer of biocompatible polymer polyethylene glycol (PEG). IL-4 was attached to the areas devoid of PEG using a chemical bond. Such a structure of nanoparticles keeps IL-4 active for a long time after being injected into muscles and absorbed by muscle immune cells.

To study the effect of gold nanoparticles carrying IL-4, as well as nanoparticles carrying IL-10 (an anti-inflammatory cytokine with a different mechanism of action) on muscles affected by Duchenne muscular dystrophy, researchers used a mouse model of Mdx, which carries a specific mutation found in patients with this disease. Since muscle degeneration occurs much slower in Mdx mice than in humans, the researchers developed an approach in which the muscles of the hind limbs of old Mdx mice were repeatedly injured, accelerating the progression of the disease. This made it possible to more accurately simulate a human disease. In Mdx mice, microtrauma caused chronic inflammation, similar to inflammation in Duchenne muscular dystrophy, which persisted for several weeks.

Active muscles with T cells

A week after the end of the microtrauma procedure, mice were injected with IL-4 and IL-10 nanoparticles directly into chronically damaged muscles and two weeks later the effects were evaluated. Cytokine therapy with IL-4, but not IL-10, significantly increased the cross-sectional area of muscle fibers. Mice after IL-4 administration showed a fourfold increase in the strength and speed of muscle contraction compared to mice in the control groups.

The group observed an increase in the number of T cells in chronically damaged muscles with nanoparticle-based cytokine therapy by 50% compared to 20% in the control, while the number of other types of immune cells, including neutrophils, dendritic cells, natural killer cells, monocytes and macrophages, remained unchanged.

Previously, macrophages in their anti-inflammatory state (M2) were proposed as a candidate for restoring muscle strength in mouse models of Duchenne dystrophy. However, in chronically inflamed muscles of the new Mdx model, M2 macrophages did not significantly contribute to the therapeutic effect.

Duchenne muscular dystrophy becomes the most life-threatening when the diaphragm and heart muscle are affected. The researchers hope that the new strategy will someday help improve breathing and restore heart function in patients. They add that the same principle of cytokine therapy based on nanoparticles can be useful for a number of other muscle disorders in which inflammation is the main link in pathogenesis.

Article by T.M.Raimondo et al. Anti-inflammatory nanoparticles significantly improve muscle function in a murine model of advanced muscular dystrophy published in the journal Science Advances.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Wyss Institute: Muscling up with nanoparticle-based anti-inflammatory therapy.

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