HomeENGLISH MAGAZINEScavengers got genetics: homing macrophages as possible target in Duchenne dystrophy

Scavengers got genetics: homing macrophages as possible target in Duchenne dystrophy

Duchenne muscular dystrophy (DMD) is a severe genetic disorder that leads to progressive muscle weakness and degeneration due to disruptions to the protein dystrophin, which helps keep muscle cells intact. It is among the most common congenital disease in the world, affecting about one out of every 5000 males, while females are very rarely affecte. DMD symptoms typically appear in early childhood, with patients facing increased loss of muscle function as they age. A classical revelatory symptom is the inability do stand up from the sitting on the floor, ability that can be reached with a complex order of movements the child coordinate with arms and wrists. As the disease progresses, many patients are forced to rely on mobility aids, such as a wheelchair, with the disease eventually impacting heart and lung function. While improvements in cardiac and respiratory care have increased life expectancy in recent decades, there is currently no practical cure. Genetic attempts are ongoning and seem to show promises.

Researchers at the University of British Columbia’s School of Biomedical Engineering have discovered that an existing cancer drug could have potential to treat this condition. The researchers found that the drug, known as a colony-stimulating factor 1 receptor (CSF1R) inhibitor, helped slow the progress of DMD in mice by increasing the resiliency of muscle fibers.The findings caught the researchers by surprise while they were initially studying the role of resident macrophages, a type of white blood cell, in muscle regeneration. They originally identified three populations of skeletal muscle blood-derived cells cells: a population of macrophages positive for lymphatic vessel endothelial receptor 1 (LYVE1+) and T cell membrane protein 4 (TIM4+), a population macrophages negative for both receptors, and a population of cells likely representing dendritic cells that were positive for CD11C and major histocompatibility complex class II (MHC-II).

During experimentation in mice, they found that CSF1R inhibitors, which deplete resident macrophages, had the unexpected effect of making muscle fibers more resistant to the type of contraction-induced tissue damage that is characteristic of muscular dystrophy. The drug had the effect of changing the type of muscle fibers in the animal’s body from damage-sensitive type IIB fibers toward damage-resistant type IIA/IIX fibers. This kind of drug is used as targeted-therapy in cancer, since they are fundamentally kinase inhibitors, even though some biologicals do the same like RG-7155 or emactuzumab that targets the CSF1R directly on the cellular surface. Pharmacological examples of CSF1R inhibitors known to researchers are those called PLX-3397, IACS-9439 and BPR1R024. After making the discovery the researchers tested the drug in mice with DMD. Within a few months of treatment, they began to see successful results.

The mice that underwent treatment showed higher frequencies of damage-resistant muscle fibres and were able to perform physical tasks, like moderate running on a treadmill, with less muscle damage than their untreated counterparts. What scientists saw what a shoft in muscle fibers typology, the chronic treatment with a CSF1R inhibitor changing them from sensitive glycolytic fibers toward damage-resistant glycolytic-oxidative one.The researchers say that further studies are needed to identify if CSF1R is effective at treating DMD in humans, even though the most surprising finding it to have shown for the first time how immune cells may be directily involved in the vlinical evlìolution of a genetic form of muscular dystrophy. Considering that several short-term clinical studies have already shown that this class of drug is safe for use in people, they’re hopeful that it could mean a patient-ready treatment will soon be at hand.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Babaeijandaghi F et al. Sci Translat Med 2022; 14(651):eabg7504.

Xu X, Hao Y et al. Pharmgenomics Pers Med. 2021; 14:431-444.

Czako B et al. J Med Chem. 2020 Sep 10; 63(17):9888-9911.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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