Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy
Abstract
:1. Duchenne Muscular Dystrophy (DMD)
1.1. Therapeutic Approaches to DMD
1.1.1. Corticosteroids
1.1.2. Cell Therapy
1.1.3. Gene Therapy
1.1.4. Exon Skipping
1.1.5. Induction of Utrophin Expression
1.1.6. Alternative Approaches
2. Sertoli Cells
2.1. Sertoli Cells: Multiple Roles for a Single Cell Type
2.2. The Immunomodulatory Properties of SeC
2.3. The Encapsulation Chance
2.4. Pre-Clinical Studies Using Microencapsulated SeC
2.5. Use of MC-SeC in DMD
3. Conclusions and Remarks
Acknowledgments
Conflicts of Interest
Abbreviations
AAV | Adeno-associated virus |
AON | Antisense oligonucleotide |
BTB | Blood-testis barrier |
DAPC | Dystrophin-associated protein complex |
DMD | Duchenne muscular dystrophy |
E-MC | Empty microcapsules |
GRMD | Golden retriever muscular dystrophy |
HDAC | Histone deacetylase |
HRGβ1 | Heregulin β 1 |
IDO | Indoleamine 2,3-dioxygenase |
IGF-1 | Insulin-like growth factor 1 |
iPSC | Induced pluripotent stem cells |
MC-SeC | Microencapsulated Sertoli cells |
NMJ | Neuromuscular junction |
NOD | Non-obese diabetic |
NRG1 | Neuregulin 1 |
PDE5 | Phosphodiesterase 5 |
SeC | Sertoli cells |
SPF | Specific-pathogens free |
TGF-β | Transforming growth factor β |
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Approach | Mechanism of Action | Positive Effects | Side Effects/Limitations | Clinical Trial | Refs. |
---|---|---|---|---|---|
Givinostat (HDAC inhibitor) | Not completely clarified in DMD.Downregulation of myostatin due to increased expression of follistatin | Improved muscle morphology and increase in myofiber size in mdx mice and DMD patients. | Platelet reduction, gastrointestinal adverse effects. | Phase II ongoing | [47,48,69] |
Tadalafil and Sildenafil (PDE5 inhibitors) | Increased levels of cGMP inducing vasodilatation. | Prevention of exercise-induced ischemia, injury and fatigue in mdx mice. | Headache, fall, upper respiratory tract infection, gastrointestinal adverse effects. | Phase III failed in protecting versus ambulatory decline | [19,49,50,70] |
Halofuginone (HT-100) | Anti-fibrotic agent | Reduction of fibrotic tissue deposition | No serious adverse effects reported for low doses | Phase II suspended for death of a patient receiving high doses | [51,71] |
Idebenone (Catena/Raxone) | Antioxidant inducing mitochondrial electron reflux and cellular energy production; inhibition of lipid peroxidation | Improved cardiac and muscle functionality in mdx mice; improved respiratory function in DMD patients | Nasopharyngitis, headache and mild diarrhoea | Phase III completed | [52,53,54] |
Ataluren (Translarna, PTC124) | Premature stop codons readthrough | Restoration of dystrophin expression in mdx mice | No severe adverse effects reported. Specific for nonsense mutations | Phase III completed | [55,56,57,58,59] |
Domagrozumab (Human anti-myostatin mAb) | Blockade of myostatin activity | Increment in muscle mass and strength in mdx mice and healthy subject | Headache, fatigue, upper respiratory tract infections, and muscle spasms. | Phase II recruiting | [60,61,62,63,64,72] |
CRISPR/Cas9 | Cleavage of specific DNA sequences to remove the mutated exon | Improved skeletal and cardiac muscle morphology and functionality in mdx mice | Mutation-dependent. No adverse effects reported | Preclinical | [65,66,67,73] |
Growth Factors/Cytokines | Immunomodulatory Factors | Maturative Factors/Hormones |
---|---|---|
BDNF (Brain Derived Neurotrophic Factor) and GDNF (Glial cell-Derived Neurotrophic Factor) | Activin A | Activins/Inhibins |
bFGF (basic Fibroblast Growth Factor) | Clusterin | Dhh (Desert hedgehog) |
EGF (Epidermal Growth Factor) | Complement cascade inhibitors | Estrogens |
HRG (Heregulin)-β1 | FasL (Fas Ligand) | KL/SCF (Kit Ligand/Stem Cell Factor) |
hSCSGF (human Sertoli Cell Secreted Growth Factor) | IDO (Indolamine 2,3-Dioxygenase) | MIS/AMH (Müllerian Inhibiting Substance/Anti Müllerian Hormone) |
IFN (Interferon)-γ | IL-2 suppressor factors | |
IGF (Insulin-like Growth Factor)-I and -II | JAG1 (soluble JAGGED1) | Antiapoptotic factors |
IL (Interleukin)-1 and -6 | MIF (Macrophages Inhibitor Factor) | BCL-w |
NT (Neurotrophin)-3 | Serpins (serine protease inhibitors) | |
PDGF (Platelet Derived Growth Factor) | TGF-β | |
SGP (Sulfated Glycoprotein-1/Prosaposin) | Transferrin | |
TGF (Transforming Growth Factor)-α and -β | ||
VEGF (Vascular Endothelial Growth Factor) |
Approach | Mechanism of Action | Positive Effects | Side Effects | Clinical Trial | Refs. |
---|---|---|---|---|---|
MC-SeC | A cocktail of antiinflammatory and trophic factors secreted by SeC reaches muscle tissue from the peritoneal cavity. Induction of utrophin expression via SeC-released HRGβ1 | Reduction of muscle inflammation, necrosis and fibrosis. Increased expression of utrophin. Improved muscle morphology and functionality; incr eased resistance to exercise-induced muscle damage | No side effects observed | Preclinical | [114,122] |
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Chiappalupi, S.; Salvadori, L.; Luca, G.; Riuzzi, F.; Calafiore, R.; Donato, R.; Sorci, G. Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy. J. Funct. Morphol. Kinesiol. 2017, 2, 47. https://doi.org/10.3390/jfmk2040047
Chiappalupi S, Salvadori L, Luca G, Riuzzi F, Calafiore R, Donato R, Sorci G. Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy. Journal of Functional Morphology and Kinesiology. 2017; 2(4):47. https://doi.org/10.3390/jfmk2040047
Chicago/Turabian StyleChiappalupi, Sara, Laura Salvadori, Giovanni Luca, Francesca Riuzzi, Riccardo Calafiore, Rosario Donato, and Guglielmo Sorci. 2017. "Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy" Journal of Functional Morphology and Kinesiology 2, no. 4: 47. https://doi.org/10.3390/jfmk2040047