Page 46 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Al-Khawaga and Abdelalim Stem Cell Research & Therapy (2020) 11:437 Page 27 of 33

improvement in absolute neutrophil count and lympho- COVID-19, obtaining a basic complete blood count
penia, with a decline in CRP, ferritin, and D-dimer. To (CBC), comprehensive metabolic panel (CMP), and key
our knowledge, this is the first published clinical study inflammatory markers, as well as measurement of key
to use IV administration of BM-MSC-derived exosomes cytokines (IL1, IL6, IL8, TNF-alpha, IL10, TGF-beta,
as treatment for COVID-19 [154]. These findings indi- sRAGE, Ang-2) at baseline and at defined time frames
cate that MSCs and their exosomes are promising op- following therapy is crucial.
tions for treating ARDS associated with respiratory viral One of the key points in designing the clinical trial is
infections. the MSC dose and route of administration. IV route is
the most commonly used method for systemic delivery
Points to consider in designing MSC clinical trials of MSCs in the majority of clinical trials, with much
for COVID-19 fewer trials using intra-arterial (IA) injection [172]. The
Only regulated and compliant clinical trials can demon- most frequently utilized route of MSC administration in
strate and provide mechanistic and translational insights ARDS and COVID-19 is also via IV infusion. Of interest,
on the role of MSCs in ALI and ARDS in COVID-19. IV route remains the most well studied route used for
Designing randomized controlled trials (RCT) with set- MSC delivery in pulmonary diseases [172]. Regardless of
ting clear inclusion and exclusion criteria will aid in lay- the site of inflammation and tissue injury, and opposing
ing the foundation for a safe and effective stem cell- to the old concept that MSCs only migrate to the site of
based therapy in COVID19. Carrying a multicenter RCT injury following IV administration, MSCs are mostly
(MRCT) versus a single center study is a decision that trapped in lungs and undergo phagocytosis within 24 h
could further enhance advancing phases of previously [173]. In the majority of clinical indications, human
successful phase 1/2 clinical trials. MRCT allows for cap- MSCs are frequently transfused IV at doses ranging from
turing adequate sample size to reach significance and 1 to 2 million cells/kg and never exceeding a dose of 12
eliminates selection bias and confounding factors [171]. million cells/kg [172, 174]. The median dose for IV route
8
However, one has to define a consensus on cell- is 1 × 10 MSCs per patient per total dose. Analysis of
characterization, inclusion/exclusion criteria, and out- MSC trials using IV route indicated minimal effective
come measures. Although there is no consensus on the doses (MEDs). Efficacy dose-response outcome data in-
criteria of MSCs clinical trials in COVID-19 as of yet, dicated a narrower MED range of MSCs ranging from
the most common inclusion criteria are confirmed 100 to 150 million, where either higher or lower has
SARS-COV-2 by RT-PCR from respiratory sample, re- been less efficient [172].
spiratory failure requiring intubation and ventilator, and
meeting criteria of ARDS (PaO 2 /FiO 2 ratio < 200 Challenges in treating COVID-19 using MSCs and
mmHg). Among the most common exclusion criteria their exosomes
are other causes of ARDS not attributed to COVID-19, One of the most significant challenges for MSC therap-
negative RT-PCR for SARS-COV-2, pregnancy, recent ies is to optimize MSC homing efficiency. IV administra-
history of thromboembolism, active malignancy, or pre- tion of MSCs shows low homing efficiency where cells
vious immunosuppressive treatment. Primary outcome get trapped in the pulmonary capillaries [175], a process
measures should aim at identifying safety and efficacy, that has been partially explained by insufficient produc-
by measuring adverse event rate and survival rate, re- tion of homing factors, such as CXCR4, on MSCs [176,
spectively. Furthermore, setting a clear time frame for 177]. It has been reported that the in vitro propagation
capturing the primary outcomes should be identified. of MSCs gradually leads to dramatic reduction in the ex-
Secondary outcome measures are also important in pression of homing factors [178, 179]. Several strategies
assessing the success of MSCs/MSC-EVs in COVID-19, have been used to improve MSC homing capacity, in-
mainly looking at long-term effects and measured thera- cluding targeted administration, genetic modification,
peutic input. Secondary outcomes measures could in- magnetic guidance, in vitro priming, cell surface modifi-
clude validated clinical assessment scoring like the cation, and radiotherapeutic techniques [180, 181].
sequential organ failure assessment (SOFA) which looks Further studies are needed to define the optimal
at multiple organ system functions (respiration, coagula- source and dose of MSCs, administration route, the time
tion, liver, cardiovascular, central nervous system, and window of MSC administration, and dose frequency
renal). Specifically, secondary outcome measure should (single vs. multiple-dose regimen). Due to MSC expres-
focus on pulmonary function (PaO 2 /FiO 2 > 200); there- sion of tissue factor (TF/CD142), which triggers the co-
fore, setting a clear lung injury assessment score at base- agulation, a pro-coagulation can be triggered ultimately
line and at defined time frames following therapy. leading to thromboembolic events following infusion.
Finally, to be able to provide mechanistic and transla- Thus, the use of anti-coagulant during MSC administra-
tional insights on the role of MSCs in ALI and ARDS in tion can be considered during administration guidelines