Page 62 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Rogers et al. J Transl Med (2020) 18:203 Page 8 of 19

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treated with a target dose of 12 × 10 ASCs. Success in The safety of MSC therapy
the primary outcome variable, Client Specif c Outcome Intravenous infusion is the most common route for MSC
Measures, was statistically improved in the treated group delivery and has been studied in hundreds of clinical tri-
compared to the placebo group (79.2% versus 55.4%). T e als [167]. Lalu et al. was the f rst to conduct a systematic
veterinary pain on manipulation score (92.8 versus 50.2) review and meta-analysis that comprehensively summa-
and the veterinary global score (86.9% versus 30.8%) were rized the safety of intravenous MSC administration in
both statistically improved in treated dogs compared to more than 1000 patients [168]. T eir analysis was unable
placebo. T ere was no detected signif cant dif erence to detect an association between MSC treatment and the
between treated and placebo dogs in the incidence of development of acute infusion related toxicity, organ sys-
adverse events or negative health f ndings. An FDA sub- tem complications, infection, malignancy or death [168].
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mitted GLP canine preclinical safety study of this same Allogeneic MSC doses up to 100 × 10 have not resulted
canine ASC product demonstrated safety at a 30X dose in serious adverse events with follow-up greater than
level [153]. T ere were no detectable signif cant dif er- 1 year in patients with sepsis, ischemic heart disease, per-
ences in the incidence of adverse events between treated ianal f stula, spinocerebellar ataxia, rheumatoid arthritis
and placebo-controlled dogs. or severe osteoarthritis [169–176]. Safety and ef cacy
In a naturally occurring lung disease in horses, ASCs were also demonstrated in several human clinical trials
were used to treat lung epithelial and alveolar pathology of immune mediated inf ammatory diseases [52–55, 177,
[154]. Exercise-induced pulmonary hemorrhage (EIPH) 178]. Based upon numerous published human clinical tri-
occurs in the majority of T oroughbred and Standard- als, the intravenous administration of BM-MSCs appears
bred racehorses [155–161], as well as other breeds that to be safe.
are required to perform strenuous exercise in their ath- T e safety of allogeneic ASCs has been studied in car-
letic disciplines (e.g. barrel racing Quarter Horses). It diovascular disease [179–182], inf ammatory bowel dis-
can lead to progressively decreased athletic performance ease [183], diabetes mellitus [184–186], kidney disease
[155–161]. EIPH causes persistent structural lung dam- [187, 188], osteoarthritis [189, 190], bone regeneration
age with f brosis and vascular remodeling of the cau- [191, 192], cirrhosis [193], multiple sclerosis [52, 194,
dodorsal lung f elds, as well as venous remodeling and 195], systemic lupus erythematosus [178, 196–198],
occasional bronchiolar damage [156, 157, 159–162]. T is, graft-versus host disease [177, 199, 200] and acute res-
in turn, leads to pulmonary hypertension, capillary stress piratory distress syndrome [92, 201]. Allogeneic MSC
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failure and hemorrhage into the lung. T ere is substan- doses up to 100 × 10 have not resulted in serious adverse
tial evidence of the ASC’s ability to reduce inf ammation, events with follow up greater than 1 year in patients with
reduce f brosis and repair damaged tissues [163–166]. sepsis, ischemic heart disease, perianal f stula, rheuma-
T erefore, ASCs were hypothesized to repair dam- toid arthritis or severe osteoarthritis [169–175].
aged vessels, prevent pulmonary capillary hemorrhage, Toyserkani, et al. conducted a systematic review of adi-
reduce pulmonary hypertension and decrease perivascu- pose derived MSC therapies that included 70 clinical tri-
lar inf ammation and f brosis in EIPH. All twelve horses als and more than 1400 patients with follow-up ranging
treated with ASCs were able to race again without any from less than a month to 3 years [202]. Very few adverse
prophylactic medications. Prior to treatment with ASCs, events have been reported that could be related directly
all 12 of the horses had obvious epistaxis after racing and to MSC therapy. One case of pulmonary thromboembo-
veterinary conf rmation of lung bleeding by tracheobron- lism was reported 4 weeks after intramyocardial stromal
choscopic (TBS) examination, despite having received vascular fraction injection in a patient with New York
pre-race prophylactic medications. Following treatment Heart Association class II heart failure [203]. Henry et al.
with ASCs, only 1 of 12 horses had epistaxis with exer- performed intramyocardial ASC injections in 17 chronic
cise. Five of eight horses (62.5%) were conf rmed Grade 0 ischemic cardiomyopathy patients with an average ejec-
EIPH (no bleeding) by post-race TBS examination. Two tion fraction of 31% and two patients suf ered possible
horses (25%) were conf rmed Grade 1 EIPH, and one TIA or stroke, but the cause could not be directly attrib-
horse (12.5%) was conf rmed Grade 2 EIPH on post-race uted to the procedure [204, 205]. T ese studies did not
TBS examination. Owner/Trainer performance evalu- describe whether the cells were f ltered before adminis-
ations following treatment with ASCs were reported on tration to ensure that the injected cells were single cell
only six horses. Four were reported as signif cantly bet- suspensions. T romboembolic complication risk can be
ter, one as better, and one as unchanged. Again, all horses assumed to be higher when injecting clumped cells com-
raced without prophylactic medications after treatment pared with single cell suspensions, particularly when
with ASCs and no treatment associated adverse events performed in intramyocardial injections. In addition,
were report. the patients’ underlying medical conditions must also be