Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for amyotrophic lateral sclerosis

Abstract

Background: In this pilot safety study, we hypothesized that a human bone marrow stem cell-derived extracellular vesicle (hBM-MSC EV) investigational product (IP) would be safe and exhibit potential efficacy in amyotrophic lateral sclerosis (ALS) patients. Methods: Ten ALS patients received two 10-ml intravenous infusions of the IP given 1 month apart and evaluated over 3 months. Results: There were no serious adverse events or adverse events related to the IP and 30% of subjects' ALS functional rating scale-revised (ALSFRS-R) scores did not decline. Conclusion: HBM-MSC EVs appear safe in ALS patients. This early investigation suggests a controlled study of EVs for the treatment of ALS is warranted.

Plain language summary

Amyotrophic lateral sclerosis (ALS) is a nervous system disease that affects the brain and spinal cord, causing the loss of muscle control. Currently, there is no cure for ALS and the disease gets worse over time. A potential new treatment is being investigated using mesenchymal stem cell extracellular vesicles (MSC EVs). MSC EVs are small structures that contain useful molecules and proteins that can be transported to cells affected by the disease, helping to reduce inflammation and encouraging repair. This 3-month study looked at the safety of human bone marrow MSC-EVs (hBM-MSC EVs) given as treatment to ten ALS patients, as well as how well it worked at delaying worsening of the disease. They found that there were no serious side effects caused by the treatment and that hBM-MSC EVs may have the potential for delaying the progression of ALS. This indicates that more, larger studies need to be carried out to find out treatment specifics, such as dose (how much of the treatment to give) and frequency (how often to give the treatment), and how they could be related to patient outcomes.

Article Highlights

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neurons that affects an estimated 6.6 persons per 100,000 individuals in the USA.

• Currently, there are no effective cures for ALS, but recent studies suggest that mesenchymal stem cell (MSC) therapy approaches may be useful.

• Extracellular vesicles derived from human bone marrow mesenchymal stem cell-derived extracellular vesicles (hBM-MSC EVs) can convey much of the immunomodulatory and regenerative activities exhibited by MSCs.

• The use of hBM-MSC EVs offers substantial practical advantages over the use of intact MSCs and may represent an improvement in ALS treatment by regenerative medicine methods.

• This prospective study was designed to explore the safety and potential for efficacy in the treatment of ALS of an advanced hBM-MSC EV preparation when provided by intravenous infusion at the study start and again after 1 month.

• No adverse events or serious adverse events were reported, suggesting the investigational product may be safe in ALS patients.

• Over the 3-month study, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores of three patients did not decline.

• Based on the safety profile and the potential for efficacy, we propose that hBM-MSC EVs be studied in more rigorous trials for the treatment of ALS.

Keywords: :

• ALS
• amyotrophic lateral sclerosis
• bone marrow mesenchymal stem cell
• extracellular vesicle

Author contributions

J Crose participated in study design, study execution, analysis, and manuscript preparation. A Crose participated in study design and operations. J Ransom and AL Lightner participated in data analysis and manuscript preparation.

Financial disclosure

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The ExoFlo™ investigational product was provided by Direct Biologics, LLC (TX, USA). J Crose is the President of Capitis Research Institute, Inc. and has no conflicts of interest in the execution and publication of this research. A Crose, at Capitis Research Institute, Inc., has no conflicts of interest to disclose. J Ransom is Senior Medical Writer at Direct Biologics and CSO at Vivreon Biosciences. AL Lightner is CMO at Direct Biologics and Consultant CMO for Boomerang Medical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The investigators followed ethical procedures to perform research on human subjects with internal IRB review prior to commencing any delivery of treatment. This study protocol was reviewed and approved by the Institute of Regenerative and Cellular Medicine Investigative Review Board, approval number IRCM-2021-296. Written informed consent was obtained from all subjects participating in the study.

Data sharing statement

Data can be shared upon request to the corresponding author.