Equine Mesenchymal Stem/Stromal Cells Freeze-Dried Secretome (Lyosecretome) for the Treatment of Musculoskeletal Diseases: Production Process Validation and Batch Release Test for Clinical Use.
Abstract: In the last decades, it has been demonstrated that the regenerative therapeutic efficacy of mesenchymal stromal cells is primarily due to the secretion of soluble factors and extracellular vesicles, collectively known as secretome. In this context, our work described the preparation and characterization of a freeze-dried secretome (Lyosecretome) from adipose tissue-derived mesenchymal stromal cells for the therapy of equine musculoskeletal disorder. An intraarticular injectable pharmaceutical powder has been formulated, and the technological process has been validated in an authorized facility for veterinary clinical-use medicinal production. Critical parameters for quality control and batch release have been identified regarding (i) physicochemical properties; (ii) extracellular vesicle morphology, size distribution, and surface biomarker; (iii) protein and lipid content; (iv) requirements for injectable pharmaceutical dosage forms such as sterility, bacterial endotoxin, and Mycoplasma; and (v) in vitro potency tests, as anti-elastase activity and proliferative activity on musculoskeletal cell lines (tenocytes and chondrocytes) and mesenchymal stromal cells. Finally, proteins putatively responsible for the biological effects have been identified by Lyosecretome proteomic investigation: IL10RA, MXRA5, RARRES2, and ANXA1 modulate the inflammatory process RARRES2, NOD1, SERPINE1, and SERPINB9 with antibacterial activity. The work provides a proof-of-concept for the manufacturing of clinical-grade equine freeze-dried secretome, and prototypes are now available for safety and efficacy clinical trials in the treatment of equine musculoskeletal diseases.
Publication Date: 2021-06-10 PubMed ID: 34200627PubMed Central: PMC8226765DOI: 10.3390/ph14060553Google Scholar: Lookup
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- Journal Article
- Biotechnology
- Cell Culture
- Cell Proliferation
- Clinical Study
- Disease Treatment
- Equine Diseases
- Equine Health
- Equine Science
- In Vitro Research
- Inflammation
- Intra-Articular Injection
- Mesenchymal Cells
- Musculoskeletal System
- Pharmaceuticals
- Proteomics
- Regenerative Medicine
- Stem Cells
- Veterinary Medicine
- Veterinary Practice
- Veterinary Research
Summary
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The research article discusses the development and testing of a freeze-dried secretome, coined as ‘Lyosecretome’, produced from equine adipose tissue-derived mesenchymal stromal cells. This experimental product is proposed as a therapeutic measure to treat musculoskeletal disorders in horses.
Preparation and Purpose of Lyosecretome
- The researchers prepared ‘Lyosecretome’, a freeze-dried secretome from adipose tissue-derived mesenchymal stromal or stem cells.
- Researchers have demonstrated that the regeneration-promoting properties of these stem cells are mostly due to the secretion of soluble factors and extracellular vesicles, termed as the secretome.
- In this study, this secretome is used to create a potential treatment for horse musculoskeletal disorders. The Lyosecretome is designed as an intraarticular injectable pharmaceutical powder.
Validation of Production Process
- The production process for the Lyosecretome was validated in a facility authorized for the production of veterinary medicinal products intended for clinical use. This step is critical to ensure safety, compliance, and effectiveness of the production process.
- Key factors for assuring product quality and batch release included physical and chemical properties, extracellular vesicle features (morphology, size distribution, and surface biomarkers), protein and lipid content, and specific requirements for injectable pharmaceutical dosage forms like sterility, absence of bacterial endotoxins and Mycoplasma contaminants.
Testing for Biological Activity
- Potency tests were also carried out to determine the anti-elastase activity and proliferative activity on musculoskeletal cell lines, including tenocytes (tendon cells), chondrocytes (cartilage cells), and mesenchymal stromal cells.
- Proteins potentially responsible for the biological effects of the Lyosecretome were also identified. Notably, these proteins are involved in regulating inflammation and possess antibacterial activity (IL10RA, MXRA5, RARRES2, ANXA1, NOD1, SERPINE1, and SERPINB9).
Significance and Next Steps
- The study acts as a proof-of-concept for creating a clinical-grade equine freeze-dried secretome, which could be crucial for treating equine musculoskeletal diseases in the future.
- Following the successful production and initial testing of the Lyosecretome, the researchers indicate that the next step will involve safety and efficacy clinical trials.
Cite This Article
APA
Mocchi M, Grolli S, Dotti S, Di Silvestre D, Villa R, Berni P, Conti V, Passignani G, Brambilla F, Bue MD, Catenacci L, Sorrenti M, Segale L, Bari E, Mauri P, Torre ML, Perteghella S.
(2021).
Equine Mesenchymal Stem/Stromal Cells Freeze-Dried Secretome (Lyosecretome) for the Treatment of Musculoskeletal Diseases: Production Process Validation and Batch Release Test for Clinical Use.
Pharmaceuticals (Basel), 14(6), 553.
https://doi.org/10.3390/ph14060553 Publication
Researcher Affiliations
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
- Department of Veterinary Medical Science, University of Parma, 43121 Parma, Italy.
- Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna, 25124 Brescia, Italy.
- Institute of Biomedical Technologies, F.lli Cervi 93, 20054 Segrate, Italy.
- Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna, 25124 Brescia, Italy.
- Department of Veterinary Medical Science, University of Parma, 43121 Parma, Italy.
- Department of Veterinary Medical Science, University of Parma, 43121 Parma, Italy.
- Institute of Biomedical Technologies, F.lli Cervi 93, 20054 Segrate, Italy.
- Institute of Biomedical Technologies, F.lli Cervi 93, 20054 Segrate, Italy.
- Freelance Veterinary Medical Doctor, 43121 Parma, Italy.
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, Largo Donegani 2/3, 28100 Novara, Italy.
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
- Institute of Biomedical Technologies, F.lli Cervi 93, 20054 Segrate, Italy.
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
- PharmaExceed S.r.l., Piazza Castello, 19, 27100 Pavia, Italy.
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
- PharmaExceed S.r.l., Piazza Castello, 19, 27100 Pavia, Italy.
Grant Funding
- ATEx-Advanced Therapies Experiences. Project ID 637541 / Interreg V-A Italy-Switzerland 2014-2020
Conflict of Interest Statement
M.L.T. and S.P. are co-founders and members of the advisory board of the company PharmaExceed S.r.l.
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Citations
This article has been cited 5 times.- Giovannelli L, Bari E, Jommi C, Tartara F, Armocida D, Garbossa D, Cofano F, Torre ML, Segale L. Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access.. Bioact Mater 2023 Nov;29:16-35.
- Mareschi K, Banche Niclot AGS, Marini E, Bari E, Labanca L, Lucania G, Ferrero I, Perteghella S, Torre ML, Fagioli F. A New Human Platelet Lysate for Mesenchymal Stem Cell Production Compliant with Good Manufacturing Practice Conditions Preserves the Chemical Characteristics and Biological Activity of Lyo-Secretome Isolated by Ultrafiltration.. Int J Mol Sci 2022 Apr 13;23(8).
- Mocchi M, Bari E, Dotti S, Villa R, Berni P, Conti V, Del Bue M, Squassino GP, Segale L, Ramoni R, Torre ML, Perteghella S, Grolli S. Canine Mesenchymal Cell Lyosecretome Production and Safety Evaluation after Allogenic Intraarticular Injection in Osteoarthritic Dogs.. Animals (Basel) 2021 Nov 15;11(11).
- Mocchi M, Bari E, Marrubini G, Bonda AF, Perteghella S, Tartara F, Cofano F, Perna GD, Giovannelli L, Mandracchia D, Sorlini M, Garbossa D, Torre ML, Segale L. Freeze-Dried Mesenchymal Stem Cell-Secretome Pharmaceuticalization: Optimization of Formulation and Manufacturing Process Robustness.. Pharmaceutics 2021 Jul 23;13(8).
- Bari E, Tartara F, Cofano F, di Perna G, Garbossa D, Perteghella S, Sorlini M, Mandracchia D, Giovannelli L, Gaetani P, Torre ML, Segale L. Freeze-Dried Secretome (Lyosecretome) from Mesenchymal Stem/Stromal Cells Promotes the Osteoinductive and Osteoconductive Properties of Titanium Cages.. Int J Mol Sci 2021 Aug 6;22(16).
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