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

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.

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.

Safety of bone marrow derived mesenchymal stem cell extracellular vesicle injection for lumbar facet joint pain.

Aim: A 3-month pilot study to evaluate the safety of injecting a bone marrow-derived mesenchymal stem cell extracellular vesicle advanced investigational product (IP) into the lumbar facet joint space as a treatment for chronic low back pain. Methods: 20 healthy adults were treated with IP injections (0.5 ml/joint) and evaluated by three functional assessments 1, 3, 7, 14, 30, 60 and 90 days later. Results: No adverse effects or complications occurred across the 3-month follow-up. There were no reports of worsening pain. After 3 months group average scores improved significantly (p < 0.0001) in the Severity Index (65.04%), Interference Index (72.09%) and Oswestry Disability Index (58.43%) assessments. Conclusion: IP injections were safe and associated with significant functional improvements.

What is this article about? Bone marrow mesenchymal stem cell derived extracellular vesicles (BM-MSC EV), a novel biologic therapeutic candidate, are a safe and promising therapeutic intervention for patients with lumbar facet joint pain, a malady that manifests as persistent low back pain (LBP). 20 adult subjects with lumbar facet joint pain received a single injection of BM-MSC EV investigational product in the lumbar facet joint space. What were the results? Follow-up was conducted through in-office and virtual visits that included outcome measures to determine the safety and efficacy of this therapy. By the 3-month end point, follow-up was successful, and no complications or adverse events were noted. Significant improvements in all three assessments of pain and disability occurred throughout the study. What do the results of the study mean? The results are promising and suggest that BM-MSC EV may represent a revolutionary treatment option with durable efficacy and minimal safety risks. Randomized, controlled clinical studies into the application of BM-MSC EV in lumbar facet joint pain should be pursued to confirm the potential benefits of this novel intervention.

A novel extracellular vesicle paradigm for the treatment of COVID-19 induced acute respiratory distress syndrome (ARDS).

Efficacy of mesenchymal stem cells (MSCs) for treatment of acute respiratory distress syndrome (ARDS) suggests bioactive bone marrow MSC extracellular vesicles (BM-MSC EVs) may be effective. A patient with severe COVID-19 associated ARDS who was presumed to expire was treated with a BM-MSC EV preparation (14 doses over two months) as a rescue treatment for refractory COVID ARDS. Near complete reversal of lung inflammation and fibrosis (per computed tomography), near complete restoration of mobility, hospital discharge (3 months) with resumption of normal activities of daily living (one year) and return to work occurred. No adverse events occurred despite repeated dosing of investigational product, highlighting safety of this potential therapy for ARDS.

Safety and Efficacy of Intravenous ExoFlo in the Treatment of Complex Regional Pain Syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is an extremely painful disorder driven primarily by inflammation. OBJECTIVES: We hypothesized that the immunomodulatory biologic, ExoFloTM, composed of bone marrow mesenchymal stem cell-derived extracellular vesicles, could be safely administered to CRPS patients and alleviate symptoms. STUDY DESIGN: Ten patients received 2 intravenous (IV) infusions, each containing 15 mL ExoFlo, on day one and day 4. A series of tests were performed at baseline (day 0, prior to infusion), week one, and months one, 3, and 6 after the second infusion. SETTING: All patients were treated in one of 2 outpatient pain management clinics in Orange County, CA. METHODS: Testing for clinical improvement included: visual analog scale of pain, brief pain inventory, 36-item short-form questionnaire, range of motion analysis, and jamar dynamometer testing. RESULTS: No serious adverse events related to ExoFlo treatment occurred. Statistically significant improvements in pain and motion assessments occurred across the patient pool. LIMITATIONS: This study was limited by its patient number enrolled (10), it lacked a control arm, and one patient who dropped out of the study. CONCLUSIONS: IV delivery of ExoFlo appears safe in patients with CRPS. In addition, ExoFlo exhibited efficacy in addressing CRPS symptoms. Given the lack of effective and safe treatments available to CRPS patients, these results suggest that further studies are warranted to explore and validate this potential treatment for CRPS.

Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicle Infusion for the Treatment of Respiratory Failure From COVID-19: A Randomized, Placebo-Controlled Dosing Clinical Trial.

BACKGROUND: Bone marrow mesenchymal stem cell (BM-MSC)-derived extracellular vesicles (ExoFlo) convey the immunomodulatory and regenerative properties of intact BM-MSCs. This study aimed to determine the safety and efficacy of ExoFlo as treatment for moderate to severe ARDS in patients with severe COVID-19. RESEARCH QUESTION: Do two doses of ExoFlo safely reduce mortality in COVID-19-associated moderate to severe ARDS compared with placebo? STUDY DESIGN AND METHODS: A prospective phase 2 multicenter double-anonymized randomized placebo-controlled dosing trial was conducted at five sites across the United States with infusions of placebo, 10 mL of ExoFlo, or 15 mL of ExoFlo on days 1 and 4. Patients (N = 102) with COVID-19-associated moderate to severe ARDS were enrolled and randomized to treatment. Adverse events were documented throughout the study. The primary outcome measure was all-cause 60-day mortality rate. Secondary outcomes included time to death (overall mortality); the incidence of treatment-emergent serious adverse events; proportion of discharged patients at 7, 30, and 60 days; time to hospital discharge; and ventilation-free days. RESULTS: No treatment-related adverse events were reported. Mortality (60-day) in the intention-to-treat population was reduced with 15 mL ExoFlo mixed with 85 mL normal saline (ExoFlo-15) compared with placebo (not significant, χ2, P = .1343). For the post hoc subgroup analyses, 60-day mortality was decreased with ExoFlo-15 compared with placebo (relative risk, 0.385; 95% CI, 0.159-0.931; P = .0340; n = 50). With ExoFlo-15, a relative risk of 0.423 (95% CI, 0.173-1.032; P = .0588; n = 24) was determined for participants aged 18 to 65 years with moderate to severe ARDS. Ventilation-free days improved with ExoFlo-15 (P = .0455; n = 50) for all participants aged 18 to 65 years. INTERPRETATION: The 15 mL dose of ExoFlo was found to be safe in patients with severe or critical COVID-19-associated respiratory failure. In participants aged 18 to 65 years, the risk reduction in 60-day mortality was further improved from subjects of all ages in the intention-to-treat population after two doses of 15 mL of ExoFlo compared with placebo. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04493242; URL: www. CLINICALTRIALS: gov.

Supplementation of fat grafts with adipose-derived regenerative cells improves long-term graft retention.

Current practice of autologous fat transfer for soft tissue augmentation is limited by poor long-term graft retention. Adipose-derived regenerative cells (ADRCs) contain several types of stem and regenerative cells, which may help improve graft retention through multiple mechanisms. Using a murine fat transplantation model, ADRCs were added to transplanted fat to test whether ADRCs could improve the long-term retention of the grafts. This study showed, at both 6 and 9 months after transplantation, ADRCs not only increased graft retention by 2-fold but also improved the quality of the grafts. ADRC-supplemented grafts had a higher capillary density, indicating ADRCs could promote neovascularization. Further cell tracking and gene expression studies suggest ADRCs may promote angiogenesis and adipocyte differentiation and prevent apoptosis through the expression of various growth factors, including VEGFA and IGF-1. Taken together, these results suggest a potential clinical utility of ADRCs in facilitating autologous fat transfer for soft tissue augmentation.

High-throughput microfluidic mixing and multiparametric cell sorting for bioactive compound screening.

HyperCyt, an automated sample handling system for flow cytometry that uses air bubbles to separate samples sequentially introduced from multiwell plates by an autosampler. In a previously documented HyperCyt configuration, air bubble separated compounds in one sample line and a continuous stream of cells in another are mixed in-line for serial flow cytometric cell response analysis. To expand capabilities for high-throughput bioactive compound screening, the authors investigated using this system configuration in combination with automated cell sorting. Peptide ligands were sampled from a 96-well plate, mixed in-line with fluo-4-loaded, formyl peptide receptor-transfected U937 cells, and screened at a rate of 3 peptide reactions per minute with approximately 10,000 cells analyzed per reaction. Cell Ca(2+) responses were detected to as little as 10(-11) M peptide with no detectable carryover between samples at up to 10(-7) M peptide. After expansion in culture, cells sort-purified from the 10% highest responders exhibited enhanced sensitivity and more sustained responses to peptide. Thus, a highly responsive cell subset was isolated under high-throughput mixing and sorting conditions in which response detection capability spanned a 1000-fold range of peptide concentration. With single-cell readout systems for protein expression libraries, this technology offers the promise of screening millions of discrete compound interactions per day.