Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access

Abstract

Neurodegenerative diseases represent a growing burden on healthcare systems worldwide. Mesenchymal stem cells (MSCs) have shown promise as a potential therapy due to their neuroregenerative, neuroprotective, and immunomodulatory properties, which are, however, linked to the bioactive substances they release, collectively known as secretome. This paper provides an overview of the most recent research on the safety and efficacy of MSC-derived secretome and extracellular vesicles (EVs) in clinical (if available) and preclinical models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, acute ischemic stroke, and spinal cord injury. The article explores the biologically active substances within MSC-secretome/EVs, the mechanisms responsible for the observed therapeutic effects, and the strategies that may be used to optimize MSC-secretome/EVs production based on specific therapeutic needs. The review concludes with a critical discussion of current clinical trials and a perspective on potential future directions in translating MSC-secretome and EVs into the clinic, specifically regarding how to address the challenges associated with their pharmaceutical manufacturing, including scalability, batch-to-batch consistency, adherence to Good Manufacturing Practices (GMP) guidelines, formulation, and storage, along with quality controls, access to the market and relative costs, value for money and impact on total expenditure.

Keywords: Brain regeneration; Exosomes; Mesenchymal stem cells; Microvesicles; Secretome; Secretome formulation.

Graphical abstract

Fig. 1

MSCs as “drug stores”. MSCs release secretome, which comprises free-soluble proteins and EVs enriched with genetic material. MSC-secretome and EVs exert multiple pharmacological effects; the mechanisms responsible for the anti-inflammatory, neuroregenerative, and neuroprotective effects are indicated. Created with BioRender.com.

Fig. 2

Following intravenous, intracerebral, and intraperitoneal injection, MSC-EVs enter systemic circulation, cross the blood-brain barrier, and reach the brain. Created with BioRender.com.

Fig. 3

The “stair” to translate MSC-secretome and EV into the clinic (and the market) is made of many steep steps, all “under” the pharmaceutical regulatory framework. Created with BioRender.com.

Fig. 4

Upstream and downstream processing choices when preparing medicinal products containing MSC-secretome and EVs. As “the product is the process”, any minimal changes introduced may affect the qualitative and quantitative composition and biological activity of the final product. However, this can be exploited to “educate” cells to produce personalized secretome/EVs. Created with BioRender.com.

Fig. 5

Excipients suitable for the formulation of MSC-secretome and EVs. Buffers stabilize the pH to appropriate values compatible with the body administration and the product stability (e.g., to minimize hydrolysis and oxidation of proteins and lipids). Salts increase the ionic concentration making the preparation isosmotic with the body fluids. Sugars and polyols have many OH groups that surround and stabilize (by H-bonds) proteins and EVs even when the water in the formulation is subtracted following freezing or freeze-drying. Finally, proteins are adsorbed on the surface of EVs, creating a protein corona that prevents EV fusion and stabilizes the lipidic layer when the water in the formulation is subtracted following freezing or freeze-drying. Created with BioRender.com.

Fig. 6

Comparison between quality by testing and quality by design, and CQAs for MSC-secretome and EVs. Modified from Ref. [174]. Created with BioRender.com.

Fig. 7

Formulation of MSC-secretome/EVs as a nasal dosage form to enhance market penetration in treating NDs. Mucoadhesive excipients should be used to increase the residence time of the liquid, semisolid or particulate formulation in the nasal cavity, while penetration enhancers should be used to improve the passage of MSC-secretome/EVs through the biological barriers. CSF = cerebrospinal fluid. Created with BioRender.com.