5.2.1. Autologous bone marrow-derived mesenchymal stroma cells

The autologous bone marrow-derived mesenchymal stromal cells (ABM-MSCs) have been reported in vivo to treat different disorders like fistulising Crohn's disease, refractory luminal Crohn's disease and chronic paraplegic SCI [76–78]. In addition to other rodent models, transplantation of ABM-MSCs has shown locomotional recovery in adult mini-pigs models after the induction of SCI [78]. After preclinical evaluation, these ABM-MSCs have been reported to make their way into phase I/II clinical trials for treatment of chronic SCIs [1, 74].

Till date, a couple of the completed clinical trials that involve ABM-MSC transplantation have provided clinical outcomes. In one of the most recent clinical trial (NCT02482194 completed in March 2016) involving ABM-MSCs to treat subacute and chronic SCIs, the transplantation procedure has been documented as safe and doable. This also reported improved sensorimotor functions as well as revealed bladder and bowel improvement [79]. The phase 1 clinical trial (NCT01325103), which has been completed in December 2012 involved ABM-MSC transplantation in patients with chronic traumatic SCIs, has reported that direct cellular transplantation into lesion site is safe, viable and may encourage sensorimotor functions. In this trail, eight patients improved lower limbs motor function, mainly in the flexor muscles of hip, while seven patients advanced American Spinal Injury Association Impairment Scale (AIS) grades to B or C and nine patients improved urological functions [80]. Another phase 1/2 clinical trial that has been completed in October 2010 involving patients of subacute thoracic SCIs has reported that following ABM-MSC transplantation, noticeable recovery was observed in five patients (45.5%). ASIA sensorimotor score increased and patients were able to walk using a support [81].

In addition to the clinical trials mentioned above, there are several ongoing clinical trials from phase 1/2 to 2/3 that involve the use of ABM-MSC transplantation in patients with chronic cervical, thoracic and lumbar SCIs. These clinical trials (NCT02574585; NCT01676441; NCT02570932; NCT01730183; NCT01446640; NCT02687672; NCT02981576; NCT02260713; NCT02923817; NCT02574572; NCT02009124) are expected to be completed in the upcoming years, and the clinical outcomes from these trials are still pending as mentioned in Table 1.

#### 5.2.2. Umbilical cord-derived MSCs

Since the clinical use of ABM-MSCs might be unfavorable due to the practice of vastly invasive method, as well as the ratio of BM-MSCs decreases while differentiation increases with passage of age, the utilization of umbilical cord blood-derived MSCs is a best substitute for BM-MSCs [82]. It has been reported that umbilical cord blood-derived MSCs can be grown for longer time period and are having maximum proliferation potential. In contrast, BM-MSCs require less time to grow and possess low proliferation capacity [82]. A study has reported the transplantation of human umbilical cord-derived MSCs into animal SCI model, which has shown that these cells were able to migrate well into the lesion site and were positive to antinuclei antibody (clone 235-10) MAB1281 [83]. Following their preclinical validation, the umbilical cord-derived MSCs have reached to phase I/II clinical trials for the treatment of chronic and/or acute SCIs [1]. One of the most recent clinical trial that involves umbilical cord

Source

Embryoderived cell

GRNOPC1

(hESCs-ODPs)

 \_

Complete,

Phase 1 Jul-2013

 Safety and tolerability with no serious fallouts

 were achieved

> subacute SCI

Subacute cervical

Phase 1/

Dec-2018

 Pending

2a

SCIs

Thoracic chronic

Phase 1/

Apr-2015

 After 5 years of clinical follow-up, absolutely no safety issues have been

documented

2

SCIs

population

AST-OPC1 HuCNS-SC

UCBMC UCBMC

Mesenchymal

ABM-MSCs Autologous

MSC

ABM-MSCs AMB-MSCs ABM-MSCs

\_

\_

Thoracic and

Phase 2 Dec-2017

 Pending

NCT02574585

http://dx.doi.org/10.5772/intechopen.73220

NCT01676441

133

lumbar chronic and complete SCI

Cervical SCI

 Phase 2/

Dec-2020

 Pending

3

\_

Subacute thoracic

Phase 1/

Oct-2010

 Noticeable five patients (45.5%). ASIA

sensorimotor

patients were able to walk using a

support

 score increased and

 recovery was observed in

[81]

2

SCI

 bone marrow

\_

Chronic traumatic

Phase 1 Dec-2012

MSCs is safe, feasible and may promote

neurological

improvements

Intralesional

transplantation

 of ABM-

NCT01325103

[80]

SCI

\_

> stem cells

Lithium carbonate

 Acute and

Phase 1/

Jan-2014

 No study results posted

NCT01471613

NCT02482194

[79]

Cellular Transplantation-Based Therapeutic Strategies for Spinal Cord Injuries: Preclinical and Clinical…

2

subacute SCI Subacute and

Phase 1 Mar-2016

and viable, resulted in improved

sensorimotor

revealed bladder and bowel

improvement

 functions and also

Transplantation

 appeared to be safe

> chronic SCI

Methylprednisolone

Chronic SCIs

 Phase 1/

Dec-2013

 UCBMC' to be safe while some recipients were

appeared to regain

function

sensorimotor

transplantation

 was observed

NCT01354483

[57]

2

and lithium

carbonate

\_

\_

 Type of therapeutic

 cells

therapy

Combination

Type of spinal

Clinical

Year of

Outcome

Clinical trials

identifiers/

References

NCT01217008

[45]

NCT02302157

NCT01321333

[52]

phase

completion

reached

cord injury


Cellular Transplantation-Based Therapeutic Strategies for Spinal Cord Injuries: Preclinical and Clinical… http://dx.doi.org/10.5772/intechopen.73220 133

5.2.1. Autologous bone marrow-derived mesenchymal stroma cells

132 Essentials of Spinal Cord Injury Medicine

support [81].

5.2.2. Umbilical cord-derived MSCs

The autologous bone marrow-derived mesenchymal stromal cells (ABM-MSCs) have been reported in vivo to treat different disorders like fistulising Crohn's disease, refractory luminal Crohn's disease and chronic paraplegic SCI [76–78]. In addition to other rodent models, transplantation of ABM-MSCs has shown locomotional recovery in adult mini-pigs models after the induction of SCI [78]. After preclinical evaluation, these ABM-MSCs have been reported to make their way into phase I/II clinical trials for treatment of chronic SCIs [1, 74].

Till date, a couple of the completed clinical trials that involve ABM-MSC transplantation have provided clinical outcomes. In one of the most recent clinical trial (NCT02482194 completed in March 2016) involving ABM-MSCs to treat subacute and chronic SCIs, the transplantation procedure has been documented as safe and doable. This also reported improved sensorimotor functions as well as revealed bladder and bowel improvement [79]. The phase 1 clinical trial (NCT01325103), which has been completed in December 2012 involved ABM-MSC transplantation in patients with chronic traumatic SCIs, has reported that direct cellular transplantation into lesion site is safe, viable and may encourage sensorimotor functions. In this trail, eight patients improved lower limbs motor function, mainly in the flexor muscles of hip, while seven patients advanced American Spinal Injury Association Impairment Scale (AIS) grades to B or C and nine patients improved urological functions [80]. Another phase 1/2 clinical trial that has been completed in October 2010 involving patients of subacute thoracic SCIs has reported that following ABM-MSC transplantation, noticeable recovery was observed in five patients (45.5%). ASIA sensorimotor score increased and patients were able to walk using a

In addition to the clinical trials mentioned above, there are several ongoing clinical trials from phase 1/2 to 2/3 that involve the use of ABM-MSC transplantation in patients with chronic cervical, thoracic and lumbar SCIs. These clinical trials (NCT02574585; NCT01676441; NCT02570932; NCT01730183; NCT01446640; NCT02687672; NCT02981576; NCT02260713; NCT02923817; NCT02574572; NCT02009124) are expected to be completed in the upcoming years, and the clinical outcomes from these trials are still pending as mentioned in Table 1.

Since the clinical use of ABM-MSCs might be unfavorable due to the practice of vastly invasive method, as well as the ratio of BM-MSCs decreases while differentiation increases with passage of age, the utilization of umbilical cord blood-derived MSCs is a best substitute for BM-MSCs [82]. It has been reported that umbilical cord blood-derived MSCs can be grown for longer time period and are having maximum proliferation potential. In contrast, BM-MSCs require less time to grow and possess low proliferation capacity [82]. A study has reported the transplantation of human umbilical cord-derived MSCs into animal SCI model, which has shown that these cells were able to migrate well into the lesion site and were positive to antinuclei antibody (clone 235-10) MAB1281 [83]. Following their preclinical validation, the umbilical cord-derived MSCs have reached to phase I/II clinical trials for the treatment of chronic and/or acute SCIs [1]. One of the most recent clinical trial that involves umbilical cord


Source

 Type of therapeutic

MSCs neuronal cells)

Autologous

derived stem cells

Spinal stem cells MSC-autologous

stem cells MSC-derived

cells

Peripheral

Autologous

Schwann cells (ahSC)

Autologous

Schwann cells (ahSC)

Autologous

ensheathing

olfactory fibroblasts

Table 1. Results of clinical trials of stem cell-based therapy for spinal cord injury.

 glia and

 olfactory

\_

 human

Rehabilitation

 Chronic lumbar

Phase 1 Jan-2018

 Pending

> and thoracic SCIs

Subacute or

Phase 1 N/A

 Pending

> chronic SCIs

 human

\_

myelinating

cells

 neural stem

NeuroRegen

Cervical and

Phase 1/

Jun-2018

 Pending

NCT02688049

2

thoracic SCIs Subacute lumbar

Phase 1 Aug-2016

 Following 1-year assessment,

were observed for serious side effects

that could be specifically the nerve harvest, cellular

transplantation

transplanted

 cells in lesion site NCT02354625

NCT01231893

http://dx.doi.org/10.5772/intechopen.73220

135

 protocol or to the

 associated to

 no signs

NCT01739023

[91]

Cellular Transplantation-Based Therapeutic Strategies for Spinal Cord Injuries: Preclinical and Clinical…

SCIs

scaffold

 neural

RMx Biomatrix

 Acute, sub-chronic

Phase 1/

Dec-2018

 Pending

2

and chronic lumbar and thoracic SCIs

cord-derived

 neural

\_

Chronic cervical

Phase 1 Dec-2022

 Pending

> and thoracic SCIs

 adipose-

\_

Acute SCIs

 Phase 1/

3 Jan-2015

 Pending

NCT02034669

NCT01772810

NCT02326662

2

differentiated

 cells

therapy

Combination

Type of spinal

Clinical

Year of

Outcome

Clinical trials

identifiers/

References

phase

completion

reached

Coadministration

hematopoietic

and feasible treatment option for SCIs

 in patients' CSF is safe

 of N-Ad-MSC

 and

cord injury

Source


Source

 Type of therapeutic

ABM-MSCs ABM-MSCs ABM-MSCs

ABM or derived MSCs

ABM-MSCs ABM-derived

cells

ABM-MSCs Autologous

mononuclear

Umbilical cord Wharton's

Placebo/XCEL-UMC-BETA

Chronic traumatic

Phase 1/

Apr-2020

 Pending

> 2a

thoracic SCIs

jelly-derived

Human umbilical cord-

Bone marrow mononuclear

SCIs

Phase 1/

Oct-2019

 Trial withdrawn

 prior to enrollment

NCT02237547

NCT02481440

2

 cells

(BMMC)

derived MSCs (allogeneic)

Umbilical

MSCs

Human autologous

adipose MSC (hAdMSC)

N-Ad-MSC

adipose

 (autologous

Hematopoietic

 stem

Traumatic lumbar

Phase 1 Oct-2012

SCIs

tissue-derived

cells

tissue-derived

\_

cord-derived

\_

Complete or

Phase 1/

Dec-2018

 Pending

2

incomplete

cervical and thoracic SCIs

SCIs

Phase 1 Feb-2010

 Following cellular

SCI patients, no safety issues were seen

and also the develop teratomas

transplanted

 cells did not [86]

transplantation

 in [85]

NCT01274975

 MSCs

 cell

 bone marrow

\_

\_

Cervical chronic

Phase 1 Dec-2016

 No study results posted

> and complete SCI

SCIs

Phase 2 Dec-2016

 No study results posted

mononuclear

\_

SCIs

Phase 2 Jun-2019

 Pending

\_

Leukapheresis-

\_

\_

\_

\_

Chronic SCI Cervical, thoracic

Phase 1/

11 Jan-2014

 Pending

2

and lumbar SCIs

Thoracic and

Phase 1/

Jun-2014

 Pending

2

lumbar SCIs Chronic traumatic

Phase 1/

Dec-2021

 Pending

2

SCI

Acute SCI

 Phase 1/

Nov-2017

 Pending

2

 Phase 2 Feb-2018

 Pending

 cells

therapy

Combination

Type of spinal

Clinical

Year of

Outcome

Clinical trials

identifiers/

References

NCT02570932

NCT01730183

134 Essentials of Spinal Cord Injury Medicine

NCT01446640

NCT02687672;

NCT02981576

NCT02260713

NCT02923817

NCT02574572

NCT02009124

NCT03003364

phase

completion

reached

cord injury

Wharton's Jelly expanded MSCs with Placebo/XCEL-UMC-BETA intervention is being evaluated against thoracic SCIs in phase 1/2a, which is expected to be completed in April, 2020 (NCT03003364). Another phase 1/2 clinical trial that was testing the use of UC-MSCs in combination with bone marrow mononuclear cells was expected to complete in October 2019; however, it was withdrawn prior to enrolment (NCT02237547). One of the ongoing phase 1/2 clinical trial that purely involves the use of allogenic UC-MSCs is evaluating its safety and viability using intrathecal injections. This trial involves patients with complete or incomplete cervical and thoracic SCIs, which is expected to be completed in December 2018 (NCT02481440).

process. Such types of peripheral myelinating cells that have shown promising results in preclinical trials for SCIs and are currently being evaluated in clinical trials include the following.

Cellular Transplantation-Based Therapeutic Strategies for Spinal Cord Injuries: Preclinical and Clinical…

http://dx.doi.org/10.5772/intechopen.73220

137

Schwann cells have been reported to display significant flexibility in performing a wide range of functions in nervous system through major involvement in ensheating and myelination of axons. Schwann cells are playing crucial regenerative role in supporting regeneration of axons in the PNS, which indicates that the uses of Schwann cell transplantation and autografting will offer regenerative role in damaged CNS [87]. Different studies have reported the differentiation of adult precursor cells into Schwann cells, including a study where precursor cells isolated from skin were able to produce myelinating Schwann cells. Upon transplantation, these Schwann cells were able to improve remyelination and supported locomotional recovery from contusion SCI [88]. Following transplantation, the Schwann cells are characterized by remyelination of damaged axons and maintaining an environment favorable for axonal regrowth by secreting important growth and trophic factors [89]. One of a renowned study has shown that a combination of Schwann cell transplantation and regulation of cyclic adenosine monophosphate (cAMP) levels by using rolipram and/or a cAMP analog (db-cAMP), might improve the overall regenerative roles of Schwann cells in treatment of SCIs [90].

In clinical trials, the autologous human Schwann cells have been evaluated in phase I trials (NCT01739023; NCT02354625) for chronic and subacute SCIs [44]. In one of the most recently completed phase 1 clinical trial, transplantation of autologous human Schwann cells (ahSC) has been evaluated in patients with subacute lumbar SCIs (NCT01739023). In the clinical outcome following 1-year assessment, no signs were observed for serious side effects that could be specifically associated to the nerve harvest, cellular transplantation protocol, or to the transplanted cells in lesion site [91]. Another phase 1 clinical trial that is utilizing ahSCs in combination with rehabilitation to treat chronic lumbar and thoracic SCIs is expected to be

The olfactory ensheathing glial cells are belong to a class of macroglia, which are involved in ensheathing demyelinated axons of olfactory neurons. In olfactory bulb, typical and transected olfactory axonal structures are able to move in, regenerate and restore damaged synaptic communications with their respective targets [92]. Moreover, transplantation of olfactory ensheathing glial cells has been reported to improve axonal remyelination within a damaged nervous system [92]. A preclinical study has reported a transplantation of adult rat's olfactory bulb-derived ensheathing glia cells in a SCI's site, where the cells filled the lesion gap through regeneration [93]. In addition to the preclinical success of olfactory ensheathing cell transplantation, a study has reported the feasibility of transplantation of autologous olfactory ensheathing cells into three spinal cord injured patients where the cells were found safe without any serious complication for up to 12 months after transplantation [94]. A subsequent study has reported that transplantation of olfactory ensheathing cells is viable and safe for promoting motor and sensory activities [95]. Therapeutically, the olfactory ensheathing cells

5.3.1. Autologous human Schwann cells

completed in January 2018 (NCT02354625).

5.3.2. Autologous olfactory ensheathing glia and olfactory fibroblasts

#### 5.2.3. Autologous adipose-derived MSCs

In comparison to the umbilical cord blood, another source that has been reported to hold more number of MSCs is adipose tissue. It had been shown that 100% of MSCs can be isolated from adipose tissues compare to 63% of isolation from umbilical cord blood [82]. Since the adiposederived MSCs have been recognized by immunosuppressant characteristics and less immunogenic behavior, they have been considered as a potential source of treatment for SCIs [84]. A study has reported that after an intravenous administration of human adipose-derived MSCs in murine models (Balb/c-nu nude mice) and humans (n = 8) clinical trial (NCT01274975) for SCIs, no safety issues were seen and also the transplanted cells did not develop teratomas [85]. The use of adipose-derived MSCs has been evaluated in phase I and I/II clinical trials for treatment of different SCIs [1, 44]. A phase 1 clinical trial that has been completed in October 2012 reported that co-administration of autologous adipose-derived MSCs' differentiated neuronal cells (N-Ad-MSC) and hematopoietic in patients' CSF is safe and feasible treatment option for SCIs [86]. Another phase 1/2 clinical trial has evaluated adipose-derived MSCs in patients with acute SCIs, which was expected to be completed in 2015; however, the clinical outcomes are still pending (NCT02034669).

#### 5.2.4. MSC-derived neural stem cells

A specific cell progeny can be derived from MSCs, which has been tested in different clinical trials that mainly involve MSC-derived neural stem cell (NSC) population. In one of the most recent phase 1 clinical trials, human spinal cord-derived neural stem cells population has been used for transplantation to treat patients with chronic cervical and thoracic SCIs. The clinical outcome form this trial is still pending as the trial is expected to be completed in December 2022 (NCT01772810). A phase 1/2 clinical trial is currently evaluating MSCs-autologous NSC transplantation together with RMx Biomatrix (3D biomatrix) as scaffold for treatment of acute, sub-chronic and chronic lumbar and thoracic SCIs, which is expected to be completed in December 2018 (NCT02326662). Another phase 1/2 clinical trial that is currently ongoing for treatment of patients with cervical and throracic SCIs is utilizing the transplantation of MSCs-NSCs in combination with "NeuroRegen" scaffolds. This trial is expected to be completed in June 2018 (NCT02688049).

#### 5.3. Peripheral myelinating cells

In addition to other type of cells, the most relevant cell types for treatment of SCIs are the peripheral myelinating cells, which are mainly damaged during primary and secondary injury process. Such types of peripheral myelinating cells that have shown promising results in preclinical trials for SCIs and are currently being evaluated in clinical trials include the following.
