Study of Epidermal Grafting Using the CelluTome Epidermal Harvesting System for the Treatment of Individual Lesions in Persons With Epidermolysis Bullosa [MT2015-36]
Phase: NA
Conditions: Epidermolysis Bullosa
Sponsor: Masonic Cancer Center, University of Minnesota

University of Minnesota 
Department of Pediatrics 
 
 
 
Study of Epidermal Grafting Using the CelluTome® Epidermal 
Harvesting System for the Treatment of Individual Lesions in Persons 
with Epidermolysis Bullosa (EB) 
CPRC #2015LS154 
MT2015-36 
 
 
 
Principal Investigator 
Christen Ebens, MD, MPH  
 
 
Co-Investigators: 
Jakub Tolar, MD, PhD  
John A McGrath, MD 
Kristen Hook, MD 
Daniel Miller, MD 
Mark J Osborn, PhD 
Ashish Gupta, MD MPH 
 
 
Biostatistician: 
Ryan Shanley, MS 
 
 
Version Date: 
 July 7, 2021 
 
 
 
Confidential 
 
 

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Revision History 
Revision 
Number 
Version Date 
Summary of Changes 
Consent 
change? 
 
11/04/2015 
original to CPRC 
n/a 
 
12/01/2015 
in response to CPRC review with additional 
clarifications; 
section 1.3 – replaced tables 1 and 2 with 
differently formatted tables 
section 8 - make separate x charts for each 
treatment arm  
n/a 
1 
10/30/2016 
Synopsis, section 4.1 and Appendix I – simplify 
transplant related inclusion criteria for Arm A as it 
does not affect safety nor interfere with the study 
endpoints 
Minor edits and clarifications: 
Study Overview, Treatment Flow and Section 2 – 
replace Tegraderm® with a non-adhering silicone 
mesh 
Clarify throughout that the pain and itching 
surveys are part of iScorEb 
Sections 8.1, 8.2, and 8.3 –clarifications and 
updates to the schedule of events, add footnote 
that Evaluations do not need to be repeated if 
recently done in association with a treatment 
study 
Section 9.1 - clarify that grade 3 and greater 
adverse events at least possibly related will be 
documented.  Delete text regarding expected 
harvest site and treated wound healing times 
Section 10.1 – clarify where endpoint data will be 
stored 
Section 11 – add 1 year to outcome measures 
Section 13 – Conduct of the Study section 
missing from previous version. 
Other minor edits/updates throughout document 
Yes 
 
1.1 
10/30/2016corrected 
Study Overview: Correction of typographic error 
to remove the word “chronic” from the description 
of key eligibility criteria. 
No 
2 
4/4/2017 
Simplified study schema 
Throughout protocol clarified that follow up donor 
assessments, and 6 week follow up recipient 
assessments may be performed remotely if 
patient/donor is unable to return to UMN. 
Section 4.1 and eligibility checklist – clarified 
definition of chimerism. 
Yes 

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Section 4.2 and donor eligibility checklist – added 
donor infectious disease panel 
Section 8.1 clarified subject only needs to take 
pre-treatment iscoreEB assessment once 
Sections 8 and 10 – removed blister testing and 
skin biopsies 
3 
11/29/2017 
Sections 4, 8.1, and eligibility checklist. Clarified 
eligibility criteria with regard to donor chimerism; 
throughout protocol noted that the device may 
possibly cause infrequent, mild scarring and/or 
hypopigmentation  
Yes 
4 
12/27/2018 
Dr. Christen Ebens new PI of study. 
Background, Section 4 and eligibility checklist 
amended to remove the word “recessive” in order 
to expand eligibility to include all genotypic forms 
of dystrophic EB 
Synopsis, section 3 – added Arms C and D 
(analogous to Arms A and B but for subjects who 
were enrolled previously) 
Sections 4.1 and eligibility checklist. Removed 
detail of how somatic reversion is proven for Arm 
B subjects given variability in relevance of 
individual tests by patient and evolving 
methodologies in the field. 
Section 8: Added optional research biopsies (Arm 
A and B) 
Section 12:Added a note to describe analysis 
plan for re-enrolled subjects. 
No 
5 
07/07/2021 
Removed Drs. Weston Miller, Paul Orchard and 
John Wagner from study team; Added Dr Gupta 
Updated language on medical photography to all 
for updates in specialized equipment as needed 
and to allow for the specialty camera to be used 
per PI discretion at the specified time points 
Updated link to MCC DSMP 
No 
 
 
PI Contact Information: 
Christen Ebens, MD, MPH  
Pediatrics – Blood and Marrow Transplant 
420 Delaware St SE, MMC 484 
Minneapolis, MN 55455 
Phone: 612-626-8094 
Email: ebens012@umn.edu 
 
 

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Table of Contents 
Study Overview........................................................................................................................................... 8 
Schema ........................................................................................................................................................ 9 
1 
1 Background and Study Objectives ............................................................................................... 9 
1.1 
Phenotype and Genotype ....................................................................................................... 10 
1.2 
Hematopoietic Cell Transplantation for Severe EB ............................................................. 10 
1.3 
Transplant Outcomes .............................................................................................................. 12 
1.4 
EB Outcomes ............................................................................................................................ 16 
1.5 
Rationale for Homotypic Epidermal Grafting ........................................................................ 18 
1.6 
Study Objectives ....................................................................................................................... 19 
2 
CelluTome® Epidermal Harvesting System ................................................................................. 19 
3 
Study Overview ................................................................................................................................. 20 
4 
Patient/Donor Selection ................................................................................................................... 21 
4.1 
Patient (Recipient) .................................................................................................................... 21 
4.2 
Skin Graft Donor (either HCT donor for the EB patient [Arm A] or EB patient 
herself/himself [Arm B]) ....................................................................................................................... 21 
5 
Study Registration ............................................................................................................................ 22 
6 
Treatment Procedures ..................................................................................................................... 22 
6.1 
EB Wounds ............................................................................................................................... 22 
6.2 
Healthy Skin Grafts .................................................................................................................. 23 
6.3 
Epidermal Transfer ................................................................................................................... 23 
6.4 
Subsequent Wound Treatment .............................................................................................. 23 
7 
Expected Risks .................................................................................... Error! Bookmark not defined. 
7.1 
Donor .......................................................................................................................................... 24 
7.2 
Recipient .................................................................................................................................... 24 
8 
Schedule of Events .......................................................................................................................... 25 
8.1 
Patient (Recipient – Arm A) .................................................................................................... 25 
8.2 
Donor (Arm A) ........................................................................................................................... 26 
8.3 
Patient (Self Donor – Arm B) .................................................................................................. 26 
9 
Adverse Event Monitoring, Recording and Reporting ................................................................ 27 
9.1 
Event Monitoring/Documentation of Donor Sites and Recipient Sites ............................. 27 

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9.2 
Event Reporting ........................................................................................................................ 28 
10 
Data Collection and Study Monitoring ....................................................................................... 28 
10.1 
Data Management .................................................................................................................... 28 
10.2 
Case Report Forms .................................................................................................................. 28 
10.3 
Data and Safety Monitoring Plan (DSMP) ............................................................................ 28 
11 
Outcome Measures ...................................................................................................................... 29 
12 
Statistical Considerations ............................................................................................................ 30 
12.1 
Trial Size .................................................................................................................................... 31 
12.2 
Analysis of Primary Endpoint.................................................................................................. 31 
12.3 
 Analysis of Secondary Endpoints ......................................................................................... 31 
12.4 
Safety Monitoring ..................................................................................................................... 31 
13 
Ethical and Regulatory Considerations ..................................................................................... 32 
13.1 
Conduct of the Study ............................................................................................................... 32 
13.2 
Ethical Considerations ............................................................................................................. 32 
13.3 
Informed Consent ..................................................................................................................... 32 
14 
References .................................................................................................................................... 32 
Appendix I – Eligibility Checklist – Patient/Recipient .......................................................................... 35 
Appendix II – Eligibility Checklist – Donor ............................................................................................ 36 
Appendix III – CelluTome Procedure Overview .................................................................................. 37 

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Study Overview 
 
Study of Epidermal Grafting Using the CelluTome® Epidermal Harvesting System 
for the Treatment of Individual Lesions in Persons with Epidermolysis Bullosa  
CPRC #2015LS154 
MT2015-36 
Few but persistent wounds often remain even after successful hematopoietic cell transplantation 
(HCT) for systemic genodermatosis epidermolysis bullosa.  We propose local wound therapy 
using epidermal skin grafting from the same donor that provided the hematopoietic graft, or from 
the same EB individual with a mosaic (naturally gene corrected) skin.  In both cases permissive 
immune system and skin chimerism is expected to enable long-term epidermal engraftment and 
wound healing.  We will use FDA approved vacuum device (CelluTome®, Regulation number 
878.4820) that enables generally scar-free harvesting of epidermis with negligible bleeding and 
minimal pain (commonly described as a sensation of warmth and mild pressure) and its transfer 
on a non-adhering silicone mesh dressing (i.e. Adaptic Touch™) to the recipient’s wound.  
 
The primary study objective is to achieve > 50% wound closure within 12 weeks of skin grafting.  
 
Secondary objectives are to [1] assess safety, longevity and functionality of grafted skin in the 
recipient over the period of 1 year, [2] measure changes in quality of life (QOL) through pain, 
itching and general QOL questionnaire via iscoreEB assessment scores and [3] safety and 
seamless, scar-free healing of the body sites of the donor from which epidermis has been 
harvested over the period of 1 year. 
 
Key Eligibility: 
Diagnosis of Dystrophic Epidermolysis Bullosa (DEB) or Junctional Epidermolysis Bullosa (JEB) 
with at least one wound and fitting into one of the following study arms: 
- More than 6 months after HCT with stable (mixed or full) donor hematopoietic engraftment  
and original transplant donor is available and agrees to be the epidermal donor for this 
study (arm A). 
- Participant has a patch of healthy unaffected skin available for autologous harvest (arm B) 
 
Target enrollment is 25 patients on arm A (graft from hematopoietic stem cell donor) and 10 
subjects on arm B (self-donor) over 3 years. Up to an additional 25 patients may re-enroll in the 
study.  Re-enrolled allogenic graft recipients will be considered Arm C (treatment and follow up 
identical to Arm A) and re-enrolled self-donor recipients will be considered Arm D (treatment 
and follow-up identical to Arm B).  
 
 
 

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Schema 
 
Treatment Flow 
 
 
 
 
 
 
 
 
Baseline: Identify and 
document up to 3 
harvest sites and 3 
regions to be treated 
(ideally noting similar 
sized lesions 
elsewhere on the 
body to be 
documented as 
controls, if able) and 
complete iscorEB
Treatment: 
Transfer 
harvested 
epidermis to 
targeted 
lesions
From Families: 
Weekly photos 
(through week 
12) of treated 
sites as able 
and donor 
sites  until 
healed (e.g. 
via 
smartphone)
6 & 12 weeks 
post, follow-up 
assessments, 
(UMN, remote, 
or local clinic) 
Follow up (at 
UMN) 
approximately 1 
year post 
treatment
Patient and donor (if applicable) follow-up at 6 weeks  +/1 week at the U of MN, their local clinic, or via remote assessment if 
photographs suggest not clinically indicated  
Patient and donor (if applicable) for follow-up at 12 weeks +/- 1 week at the U of MN, their local clinic, or via remote assessment 
If at 12 weeks wound healing is good with no significant toxicity, the controls and/or other wounds may be treated (up to 3 wounds per 
time, no closer than 12 weeks apart) – refer to section 6.4   
Parent submits weekly digital photos of donor harvest site and wounds* 
Identify and document up to 3 regions for treatment and approximately equal control* (untreated) wounds 
Patient and donor (if applicable) return to the UMN for follow-up 1 year +/- 3 months (final study visit for primary and secondary 
endpoints). After each year of treatments, patients may re-enroll on study (Arms C & D). 
Identify Donor Skin Availability:  
Arm A:  graft from HCT donor  
Arm B:  self- donor – intact skin patch 
Harvest donor cells from up to three sites using Cellutome; transfer via a non-adhering, open-mesh silicone dressing to 3 regions / 
wound sites (refer to appendix III for procedure overview) 
*If possible

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1 
Background and Study Objectives 
 
Skin—like bone marrow—is a complex immune tissue that can be harvested and 
transplanted.  This unique capacity has been used with significant success in the field of 
hematopoietic cell transplantation and in practice of skin grafting.  This study aims to 
merge these concepts for the benefit of patients with systemic blistering disease, 
epidermolysis bullosa (EB). 
1.1 Phenotype and Genotype 
EB is a group of heritable mechanobullous skin diseases characterized by skin 
fragility, blister formation, and scarring.  The most severe forms of EB are 
characterized by mutilating scarring, blisters over large proportions of the body 
surface and later on, mitten deformities, joint contractures, esophageal strictures, 
corneal erosions, chronic cutaneous infections and aggressive squamous cell 
carcinoma (SCC)1-3.  Children and adults with  dystrophic EB (RDEB) and 
junctional EB (JEB) are often faced with a life of pain, often dying of SCC. SCC 
can appear as early as 13 years of age with 50% having SCC if they survive to 
age 40 years.  The prognosis of a EB patient with SCC is very poor with nearly all 
dying of metastatic disease.  Patients with the severe DEB have profound physical 
disabilities. Daily activities (e.g., toileting, feeding, bathing, walking) are major 
challenges.  Quality of life also tends to decline with age.  Caretakers are 
consumed by the day to day care of the child with EB. 
DEB is caused by loss of function mutations in COL7A1 gene and JEB by loss of 
function mutations in LAMA3, LAMB3, LAMC2 or COL17A1 genes. Type VII 
collagen (C7) is synthesized by human keratinocytes and fibroblasts alpha 3, beta 
3 or gamma 2 chains of laminin 332 (L332), and type XVII collagen (C17) are 
synthesized in keratinocytes.  These proteins are secreted around the basement 
membrane zone (BMZ) lying between the epidermis and dermis of skin. C7 is the 
major component of anchoring fibrils (AF), which are necessary for normal 
epidermal-dermal adherence, L332 and C17 are operational in structures that 
attach keratinocytes to the skin basement membrane or keratinocytes to each 
other. DEB and JEB are typically inherited as autosomal  disease with blisters and 
scarring often present at birth or shortly thereafter.  The blisters in the neonate 
often cover the whole body, including oral and esophageal mucosa, and it 
continues throughout life.  
1.2 Hematopoietic Cell Transplantation for Severe EB 
To begin to address the lack of effective therapies for DEB, in 2008 we started a 
clinical trial of hematopoietic cell transplantation (HCT) in children with generalized 

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severe DEB.  The rationale for this intervention was based on murine data showing 
that HCT could lead to restoration of c7 in the skin basement membrane of col7a1-
/- mice as well as to their improved survival.5,6  The first human study of HCT for 
DEB was reported in 2010.7  Analysis of the skin of six children in this trial showed 
that, in most subjects, donor cells engrafted in recipient skin.  Moreover, in five of 
six individuals this was paralleled by increase of C7 expression at the dermal-
epidermal junction (DEJ), healing of mucocutaneous lesions, and improved quality 
of life.7  
Nevertheless, none of the HCT recipients has become entirely free of wounds, and 
several children experienced severe complications, including death, as a result of 
the HCT-related toxicities of the high-dose chemotherapy used for myeloablative 
conditioning (MAC), of DEB disease progression, or both.  Therefore, with the 
ultimate aim of improving the efficacy and safety of HCT for the systemic and 
durable therapy of generalized severe DEB, we sequentially modified the HCT 
treatment protocol with the addition of supplemental cells and reduced intensity 
conditioning (RIC).  The addition of mesenchymal stem/stromal cells (MSCs) was 
based on identification of non-hematopoietic donor cells in the skin after HCT,7 on 
the capacity of mesenchymal stromal/stem cells (MSCs) to secrete C7, and on the 
immune-modulatory potential of these cells to mitigate graft-versus-host disease.  
The change of conditioning to RIC was adopted to assess whether less-than-
complete hematopoietic chimerism could mediate adequate clinical responses 
while being expected to result in less morbidity and mortality after allogeneic HCT.8 
In a cohort of patients with JEB, two children were transplanted using the MAC 
and four using the RIC.  Four of six patients died between days 42 and 146 after 
HCT, predominantly from progression of their primary genodermatosis.  As severe 
JEB is genetically heterogeneous, it is relevant to note that the two surviving 
individuals with severe JEB have loss-of-function mutations in LAMA3 gene, while 
those who died had genetic inactivation of LAMB3 and, in one case ITGB4 gene.  
As only six JEB patients have been treated since the study was opened there are 
still too few to accurately assess outcome/efficacy for this subgroup.  Thus the 
review below has been confined to the 26 DEB patients. 
Of the 26 individuals who underwent HCT, 13 were treated with MAC: busulfan 
(0.8 mg/kg of body weight per dose for children who weighed 12 kg or more, and 
1.1 mg/kg for those who weighed less than 12 kg, delivered intravenously every 6 
hours on days -9 to -6 before transplantation, with dose modifications based on 
pharmacokinetics, targeting 1,000 μmol per minute for the area under the curve), 
fludarabine (25 mg/m2 of body surface area per day, given intravenously on days 
-5 to -3 before transplantation), and cyclophosphamide (50 mg/kg per day, given 

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intravenously on days -5 to -2 before transplantation).  An additional 13 patients 
were treated with RIC: cyclophosphamide (50 mg/kg per day, given intravenously 
on day -6 before transplantation), fludarabine (40 mg/m2 of body-surface area per 
day, given intravenously on days -5 to -2 before transplantation), horse anti-
thymocyte globulin (30 mg/kg per day, given intravenously on days -4 to -2 before 
transplantation), and total body irradiation (200 cGy for the first seven patients in 
the RIC cohort or 300 cGy for the following six patients, delivered on day -1 before 
transplantation).  On the day of transplantation, patients received unfiltered marrow 
stem cells or umbilical cord blood cells from HLA-matched or partially HLA-
matched related or unrelated donors; after 4 hours they also received third-party 
HLA-unmatched MSCs (2 million cells/kg of body weight). Immunoprophylaxis 
against graft-versus-host disease (GvHD) consisted of cyclosporine (targeting 
trough levels of 200 to 400 μg per liter from day -3 before transplantation to day 
+100 after transplantation, with the dose tapered by 10% each week thereafter) 
and mycophenolate mofetil [15 mg/kg from day -3 before transplantation to day 
+30 (RIC) or day +45 (MAC) after transplantation]. 
1.3 Transplant Outcomes 
The overall probability of 2-year survival in the MAC cohort (n=13) was 69% (95% 
CI, 37-87%) versus 90% (95% CI, 47-99%) for the RIC cohort (n=13; p=0.3). Of 
the 20 recent DEB patients, three individuals died before one year after HCT 
(MAC: RII-4 of veno-occlusive disease, RII-7 of fungal sepsis; RIC: RIII-6 of fungal 
sepsis); one patient died after one year (MAC: RII-3 of extensive chronic GvHD; 
Tables 1 and 2).  Three individuals did not engraft with donor cells (MAC: RII-2, 
RIC: RIII-4, RIII-8; Tables 1 and 2).  There were no statistically significant survival 
differences between related versus unrelated grafts, bone marrow versus umbilical 
cord blood grafts, and those who received additional MSCs versus those who did 
not.  One individual in each cohort (MAC: RII-7, RIC: RIII-9) developed acute 
GvHD (grade 2, with stage 3 skin involvement - erythroderma); one individual 
developed extensive chronic GvHD (MAC: RII-3).  Neutrophil and platelet 
engraftment were faster in the RIC group compared to the MAC group, although 
this improvement was not statistically significant when those with autologous 
recovery were excluded from analysis.  Probably related to differences in quality 
and pace of immune reconstitution, we observed many fewer infections for RIC 
compared to MAC.  While the incidence of blood bacterial infections was similar, 
and the incidence of viral infections was not statistically different.  Remarkably, 
there was only one systemic fungal infection among the RIC-treated patients 
(versus 6 of 13 in the MAC-treated patients). 

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Table 1. Patient characteristics, grafts, and outcomes after hematopoietic cell transplantation for  dystrophic epidermolysis bullosa. 
Pt ID 
Gender 
Age in 
years at 
HCT 
Conditioning 
Graft 
Clinical features1 
Clinical outcome 
Mucocutaneous 
chimerism % 
Type VII 
collagen 
expression 
Anchoring fibrils 
(AFs) 
BSA change 
% 
RII-1 
F 
2 
MAC 
UCB,  
MSC 
Bloody emesis, corneal 
abrasions, anal fissure 
Stable 
11-30 
Increased 
Rare thick AFs; no 
C7 immune label 
75 → <25 
RII-2 
F 
9 
MAC 
UCB,  
MSC 
Esophageal strictures 
2nd HCT, no 
engraftment 
0 
Increased2 
Rare thick AFs with 
C7 immune label 
No change 
RII-3 
M 
13 
MAC 
UCB,  
MSC 
Pseudo-syndactyly, IDA, 
esophageal strictures, 
wheelchair bound 
Death 
7-33 
None 
Rare thick AFs with 
C7 immune label 
No change 
RII-4 
F 
1 
MAC 
MSD, 
MSC 
Neonatal seizure 
Death 
5-6 
None 
Thin AFs; no C7 
immune label 
75 → <5 
RII-5 
M 
5 
MAC 
MSD, 
MSC 
Esophageal strictures, 
aspiration pneumonia 
Improvement 
6-48 
None 
Thick AFs with 
moderate C7 immune 
label 
75 → <5 
RII-6 
M 
4 
MAC 
URD, 
MSC 
Neonatal sepsis, pneumonia, 
colitis, esophageal strictures, 
constipation 
2nd HCT, 
improvement 
3-22 
None 
Thick AFs; no C7 
immune label 
75 → <5 
RII-7 
M 
10 
MAC 
MSD, 
MSC 
Neonatal intubation, esophageal 
strictures, Pseudo-syndactyly, 
corneal erosions, contractures, 
IDA 
Death 
11-97 
Increased 
Thin AFs with C7 
immune label 
No change 
1 All patients had: >55% skin surface covered with erosions and blisters; history of skin colonization and infections; FTT; pruritus, and pain.  2total nucleated cells/kilogram of recipient’s body weight. 
Four hours after hematopoietic cells, all patients received single intravenous dose of 2 x 106 HLA-unmatched (3rd party) mesenchymal stromal cells. 2The C7 increase occurred early after HCT (day 
28) and later comparisons were not possible, or indicated.   
Legend:  HCT, hematopoietic cell transplantation; BSA, body surface area; MAC, myeloablative conditioning; UCB, umbilical cord blood; MSC, mesenchymal stromal cells; C7, collagen type VII; IDA, 
iron-deficient anemia.  
 
 
 
 
 
 
  

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Table 2A. Patient characteristics, grafts and outcomes for DEB with reduced intensity conditioning (RIC, 200cGy TBI). 
Pt ID 
Gender 
Age in 
years at 
HCT 
Conditioning 
Graft 
Clinical features1 
Clinical 
outcome 
Mucocutaneous 
chimerism % 
Type VII 
collagen 
expression 
Anchoring fibrils 
(AFs) 
BSA change 
% 
RIII-1 
M 
20 
RIC 200 TBI 
URD, 
MSC 
Severe contractures, wheelchair 
bound, pseudo-syndactyly, IDA, 
dental carries, depression 
Improvement 
9-23 
Increased 
Common thin AFs with 
moderate C7 immune 
label 
90 → <10 
RIII-2 
F 
2 
RIC 200 TBI 
MSD, 
MSC 
Bloody emesis, corneal abrasions Improvement 
0-2 
Increased 
Arching AFs; no C7 
immune label 
75 → <15 
RIII-3 
F 
6 
RIC 200 TBI 
MSD, 
MSC 
Esophageal strictures, corneal 
abrasions 
Improvement 
3-7 
Continuous 
Thick AFs with 
moderate C7 immune 
label 
75 → <5 
RIII-4 
F 
7 
RIC 200 TBI 
UCB,  
MSC 
Esophageal strictures, corneal 
abrasions 
No 
engraftment 
0 
None 
Thin AFs; no C7 
immune label 
No change 
RIII-5 
M 
0.75 
RIC 200 TBI 
URD, 
MSC 
Hygroma, IDA, FTT,  corneal 
abrasions 
Improvement 
0-15 
Increased 
Arched AFs with 
moderate C7 immune 
label 
75 → <5 
RIII-6 
M 
3 
RIC 200 TBI 
URD, 
MSC 
Esophageal strictures, corneal 
abrasions  
Death 
8-11 
Increased 
Thick AFs; no C7 
immune label 
No change 
RIII-7 
F 
0.9 
RIC 200 TBI 
URD, 
MSC 
Bloody emesis 
Improvement 
0-3 
None 
Thin AFs; no C7 
immune label 
75 → <5 
1 All patients had: >55% skin surface covered with erosions and blisters; history of pruritus and pain.   
Four hours after hematopoietic cells all patients received single intravenous dose of 2 x 106 HLA unmatched (3rd party) mesenchymal stromal cells 
Legend: DEB, dystrophic epidermolysis bullosa; cGy, centigray; TBI, total body irradiation; HCT, hematopoietic cell transplantation; BSA, body surface area; URD, unrelated donor; 
MSC, mesenchymal stromal cells; IDA, iron-deficient anemia; C7, collagen type VII; FTT, failure to thrive. 
 
 

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Table 2B. Patient characteristics, grafts and outcomes for DEB with reduced intensity conditioning (RIC, 300cGy TBI). 
Pt ID 
Gender 
Age in 
years at 
HCT 
Conditioning 
Graft 
Clinical features1 
Clinical 
outcome 
Mucocutaneous 
chimerism % 
Type VII 
collagen 
expression Anchoring fibrils (AFs) 
BSA change 
% 
RIII-8 
M 
3 
RIC 300 TBI 
MSD, 
MSC 
Esophageal strictures 
2nd HCT, 
improvement 
0-16 
None 
Arching AFs with C7 
immune label 
75 → <5 
RIII-9 
F 
1 
RIC 300 TBI 
MSD, 
MSC 
Severe oral mucosa blistering 
Improvement 
0-22 
Continuous 
Numerous thin AFs with 
light C7 immune label 
75 → <5 
RIII-10 
M 
0.9 
RIC 300 TBI 
MRD, 
MSC 
Corneal abrasions 
Improvement 
0-47 
Continuous 
High density AFs with 
heavy C7 immune label 
75 → <10 
RIII-11 
F 
4 
RIC 300 TBI 
MSD, 
MSC 
Esophageal strictures, corneal 
abrasions 
Improvement 
0 
None 
Rare thick AFs with light 
C7 immune label 
75 → <10 
RIII-12 
F 
0.3 
RIC 300 TBI 
URD, 
MSC 
Mild oral mucosa blistering 
Improvement 
3-8 
None 
Numerous thin AFs with 
moderate C7 immune 
label 
55 → <5 
RIII-13 
M 
0.5 
RIC 300 TBI 
MSD, 
MSC 
Moderate oral mucosa blistering 
Improvement 
13 
Continuous 
Thin AFs; no C7 
immune label 
55 → <5 
 
1 All patients had: >55% skin surface covered with erosions and blisters; history of pruritus and pain.  Four hours after hematopoietic cells all patients received single intravenous dose 
of 2 x 106 HLA unmatched (3rd party) mesenchymal stromal cells.. 
Legend:  DEB, dystrophic epidermolysis bullosa; cGy, centigray; TBI, total body irradiation; HCT, hematopoietic cell transplantation; BSA, body surface area; MSD, matched sibling 
donor; MSC, mesenchymal stromal cells; C7, collagen type VII.

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1.4 EB Outcomes 
The underlying hypothesis was that infusion of bone marrow or umbilical cord 
blood from a healthy unaffected donor will correct C7 deficiency and reduce skin 
fragility in generalized severe DEB.  A secondary hypothesis was that changes in 
conditioning intensity (from MAC to RIC regimen), and composition of the graft 
(addition of MSCs) will be well tolerated.  Further, we hypothesized that the 
changes made to the transplantation regimens would result in permanent 
hematopoietic donor engraftment that can serve as a source of renewable cells for 
the healing of mucocutaneous wounds and translate to long-term clinically 
meaningful benefits.  
Hematopoietic engraftment was near-complete in those treated with MAC.7  As 
expected with lower doses of conditioning chemotherapy, engraftment was 
significantly lower in those treated with RIC—on average 26% for CD15 cells and 
55% for CD3 cells +100 days after HCT. In agreement with standard-of-care, when 
we observed declining CD3 chimerism, we infused additional donor T cells (donor 
lymphocyte infusions, DLI).  In five of six individuals treated with DLI (Table 2), this 
intervention correlated with stabilization of grafted hematopoietic cells.  Based on 
data from disease models of DEB13 and observations of no blistering in human 
obligate heterozygotes of pathogenic COL7A1 mutations (e.g., parents of children 
with generalized severe DEB), the relative number of wild-type skin cells capable 
of ameliorating blistering is likely to be less, perhaps significantly less, than 50%.  
We therefore assessed the proportion of donor cells in skin biopsies after HCT.  
The maximum skin chimerism in those subjects with successful hematopoietic 
engraftment averaged 31% in the MAC (HSC + MSC) cohort, compared to 14% in 
the RIC group (Tables 1 and 2). Thus skin chimerism correlated proportionally with 
hematopoietic cell findings. 
We observed an increase in C7 immunolabeling in 2 of 7 DEB individuals treated 
with MAC (RII-1 and RII-7; in addition to those reported previously7), and in 4 of 
13 individuals treated with RIC (RIII-1, RIII-2, RIII-5 and RIII-6).  The increase in 
C7 was long-lasting.  This finding supports a mechanistic model whereby engrafted 
bone marrow serves continuously as a source of cells capable of migration to 
injured skin and secretion of C7.  In four other subjects in the RIC group, however, 
any changes in C7 expression after HCT were less obvious because, despite 
severe clinical phenotype, their baseline C7 immunoreactivity was bright before 
HCT (RIII-3, RIII-9, RIII-10, RIII-13), and thus any increase could not be picked up 
by a change in immunosignal intensity.  Those subjects with graft failure or early 
death were not evaluable.  Similar to the one individual reported previously,7 after 
HCT several individuals in the current trials showed no detectable increase in C7 

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at the basement membrane zone, often despite clinical improvement (Tables 1 
and 2) and favorable changes in functional skin stability. Of note, although we 
observed anti-C7 antibodies in serum before and after HCT, there was no evidence 
of anti-type VII collagen immune complexes (indirect immunofluorescence with 
binding to the base of salt split skin) after HCT (data not shown).  
Reconstitution of AFs at the DEJ following HCT is regarded as a prime indicator of 
structural and functional (physiologic) correction of the inherited skin pathology. 
Therefore, we evaluated absence or presence of AFs in skin of the clinical trial 
subjects before and after HCT using transmission electron microscopy of fixed and 
C7 antibody-labeled skin biopsies.  In some individuals (for example, RII-1) we 
saw no AFs despite increased immunohistochemical C7 expression after HCT; in 
others (for example, RIII-1 and RIII-10) AFs were seen after HCT that demonstrate 
at least two of the three defining criteria of normal AFs, i.e., insertion into the lamina 
densa, arching and/or looping profiles, and central cross-banding.14,15  Moreover, 
for some of the more uncertain wisp-like fibrils seen inserting into the lamina densa 
in some subjects (for example, RIII-1 and RIII-10), we were able to demonstrate 
immuno-ultrastuctural localization of C7 (for both C7 non-collagenous domain NC-
1 (antibody 185) and/or C7 non-collagenous domain NC-2 (LH24 antibody) at the 
sites of AF-like structures at the DEJ, providing evidence for the generation of at 
least rudimentary AFs.  TEM evaluations were frequently problematic due to high 
concentrations of “ground substance” at the DEJ in the vicinity of where anchoring 
fibrils would be expected (for example RII-5, RIII-5 and RIII-9).  This substance 
was commonly flushed away during extensive washes prior to fixation in the 
samples prepared for immuno-EM, making it more likely that anchoring fibrils 
would be identified (for example, RIII-1 and RIII-10) in samples prepared for 
immunocytochemistry. 
Given that our ultimate goal for DEB individuals is functional skin correction, we 
assessed the skin’s integrity before and after HCT in a quantitative way.  We 
employed a suction blister device whereby constant negative pressure is applied 
to the skin and the time to blistering is proportionate to the capacity of skin layers 
to adhere to each other.  Since AFs mediate connectivity of the epidermis to the 
dermis, the length of time the skin is able to withstand the application of negative 
pressure is a measure of C7 expression, polymerization, and its functional 
integration in skin.  Typically, individuals with DEB experience blistering within 10 
minutes, healthy people in approximately 60 minutes, and the heterozygous 
carriers of  COL7A1 mutations in 30-50 minutes.  Of note, in several representative 
examples from both the MAC and RIC trials, serial assessments of DEB subjects 
after HCT showed gradual increases in skin resilience under pressure.  

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Wound healing, the most striking and desired metric, has been dramatically 
improved in all but two surviving and engrafted individuals (Tables 1 and 2), as 
evidenced by both objective (serial clinical assessments and photographs) and 
subjective measures (Parental Statements).  As described in the latest 
classification of inherited epidermolysis bullosa,1 DEB individuals with the 
generalized severe form have a disorder that is systemic.  Thus individual metrics 
of biochemical, structural, and physical changes in skin, including the compound 
measure of functional skin stability with the suction blister device, do not entirely 
capture the complex pathology.  Nor do these measurements encompass the 
impact of RDEB on the health of individuals with it or the disease burden on their 
daily lives.  To tackle this issue and determine the overall effect of HCT on the 
natural history of REB, we employed the composite, recently validated, iScorEB 
tool to assess disease severity and quality of life10.  In addition, there were 
statistically significant decreases in total number of red blood cell transfusions in 
peri-transplant period (MAC versus RIC, 22.3 versus 6.3 transfusions, p-value 
0.003), in number of days spent in the hospital (MAC versus RIC, 74.8 versus 38 
days, p-value 0.01).   
1.5 
Interim Results as of September 2018 
Interval assessment completed in September of 2018 included 9 DEB subjects 
enrolled on Arm A. No subjects have been treated on Arm B. Assessment of the 
initial round of CelluTome grafting for the first 9 subjects on Arm A included a total 
of 18 grafted wounds. The mean decrease in wound surface area at 12 weeks 
post-grafting was 85.6% (range 24.4-100%). Eight wounds assessed at 1 year 
post-grafting showed a mean decrease in wound surface area of 85.6% (range 44-
100%). Donors universally had no scarring. Given these remarkable responses, 
we amended the protocol to allow for re-consenting and data collection on 
additional rounds of grafting for enrolled subjects lacking adverse events after 1 
year on study. 
1.6 
Rationale for Homotypic Epidermal Grafting  
The biological premise of this protocol is immune tolerant environment generated 
by hematopoietic cell transplantation (HCT) from related donor, either human 
leukocyte antigen (HLA) identical or HLA haplo-identical family member, followed 
by superficial epidermal grafting from the same donor.  In an alternative, though 
less common (only 10-30% of EB patients have identifiable mosaic skin patches), 
scenario the same superficial epidermal grafting procedure will be used to transfer 
mosaic (naturally gene corrected) skin from one body site to another in the same 
individual, regardless of HCT. In both cases permissive immune system and skin 

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chimerism is expected to enable long-term epidermal engraftment and wound 
healing.  
 
Such potential of long-term skin repair is based not only on the immune tolerance, 
however, but also on composition of the skin graft.  As in bone marrow, in skin a 
small fraction of cells (typically less than 1%) are stem cells capable of symmetrical 
(which generates two stem cells) and asymmetrical cell division (which generates 
one stem cell and one differentiated cell).  These tissue-specific hematopoietic and 
epidermal stem cells are the source of continual tissue regeneration and—after 
their respective transplantation—prerequisite of reconstitution in the new site.  In 
skin stem cells reside in bulge of hair follicles, inter-follicular dermis and epidermis.  
The latter will be captured in the proposed harvesting of epidermis, as both basal 
and supra-basal layers of skin contain skin stem cells (quiescent progenitors) and 
transient-amplifying cells (proliferating progenitors). 
1.7 Study Objectives 
The primary study objective is to achieve > 50% wound closure as measured on 
a per wound basis within 12 weeks of skin grafting. 
 
Secondary objectives are to: 
1. assess safety, longevity and functionality of grafted skin in the recipient at 1 
year  
2. measure changes in quality of life ( QOL) through pain, itching and general 
QOL questionnaire via iscorEB assessment score 
3. safety and seamless, scar-free healing of the body sites of the donor from 
which epidermis has been harvested over the period of 1 year 
2 
CelluTome® Epidermal Harvesting System  
The CelluTome® is a vacuum device that is applied to an area of skin and left on for 
approximately 30 minutes.  Via gentle negative pressure, it slowly raises a series of small 
(millimeters in diameter), thin epidermal skin grafts that are then sheared off via a 
disposable blade within the apparatus.  The grafts then adhere to a square of non-
adhering silicone mesh dressing and are ready for grafting to another site.  A similar piece 
of silicone mesh is then applied to the area of harvested skin as a wound dressing.  Refer 
to appendix III for an overview of the process. 
 
While similar devices have existed for years, the Cellutome has several novel 
transformative properties.16-19 Harvesting  causes only possible mild discomfort (warmth 
and pressure), infrequent, mild scarring and/or hypopigmentation , and results in minimal 

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(if any) bleeding for the donor.  Further, the device is significantly more automated and 
yields much more standardized grafts than prior iterations of this device.  The potential 
for operator error or suboptimal specimens during blister grafting has been significantly 
diminished.   
 
3 
Study Overview 
This is a single-institution pilot study to determine the capacity of immune-syntonic 
epidermal grafting to achieve > 50% wound closure as measured on a per wound basis 
within 12 weeks of skin grafting in individuals with the generalized severe forms of 
epidermolysis bullosa, DEB and JEB.  Up to 3 uninfected regions (or infected regions if 
previously treated prior to grafting) will be identified tor treatment with similar size wounds 
identified as controls if possible (no treatment). 
Wound reassessments will be performed via weekly photographs through week 12 (as 
able) and at follow up visits (either remote or at the University of Minnesota) approximately 
6 and 12 weeks after epidermal grafting. Whenever possible, assessments at the 
University of Minnesota will be scheduled as part of post-transplant follow-up visits.  In 
addition, safety, longevity and functionality of grafted skin will be monitored in the recipient 
over the period of 1 year, as well as, safety and seamless, scar-free healing of the body 
sites of the donor from which epidermis has been harvested over the period of 1 year.  
 
Although the procedures are identical, this study will have two treatment arms based on 
the source of the epidermis donor cells:  
 
Arm A:  Epidermis donor cells are from the original hematopoietic stem cell donor.  This 
arm requires two separate consents – one for the donor and one for the patient  
 
Arm B:  The patient is his/her own donor for the epidermis cells.  This arm requires a 
single consent explaining both the harvest procedures and the graft procedures. 
 
Targeted enrollment over 3 years is 25 patients for Arm A and 10 patients for Arm B.   
 
Up to 25 additional patients may re-enrolled on the study. Re-enrolled allogenic graft 
recipients will be considered Arm C (treatment and follow up identical to Arm A) and re-
enrolled self-donor recipients will be considered Arm D (treatment and follow-up identical 
to Arm B). 
 

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If at least 12 weeks after the initial grafting there are good outcomes and no unacceptable 
side effects we will offer to treat the “control” and/or other wounds in a serial fashion with 
up to three treatment sessions anticipated. Results of subsequent sessions and re-
enrolled subjects will be reported within this study, but only the primary/first treatment 
session will count toward the  primary and secondary endpoints.  Refer to section 6.4 for 
additional details. 
4 
Patient/Donor Selection 
4.1 
Patient (Recipient) 
• Diagnosis of Dystrophic Epidermolysis Bullosa (DEB) or Junctional 
Epidermolysis Bullosa (JEB) with at least one wound, visibly free from 
infection (or previously treated) and meets the eligibility for Arm A or Arm B 
based on the skin graft source: 
• Cell harvest from previous HCT donor (Arm A) – not applicable if Arm B 
- At least 6 months after HCT with donor chimerism  
• Peripheral blood donor chimerism should be measured within 21 
days of grafting and be >/= 5% and stable. Stability of chimerism will 
be determined by the protocol team and based on 3 peripheral blood 
chimerism values at least 1 month apart. 
- No history of pre-BMT autoimmune cytopenias 
- Off immune suppressive therapy 
- Original transplant donor is available and willing to be the epidermis 
donor 
• Self-donation (Arm B) – not applicable if Arm A 
- Proven somatic reversion  
- Site for skin grafting free of cellulitis and any other clinically evident 
abnormalities 
- Meets donor eligibility (section 4.2) 
• Insurance pre-authorization for procedure, if applicable 
• Voluntary written consent (patient or parent/guardian for minors with 
assent) prior to any research related procedures or treatment.   
4.2 
Skin Graft Donor (either HCT donor for the EB patient [Arm A] or EB 
patient herself/himself [Arm B]) 
• Age > 2 years (based on prior safety testing of the device) 
• Healthy on physical examination in the opinion of the evaluating provider 
• Negativity for Hepatitis B and C, HIV, and HTLV1/2 within 30 days of 
donation. 

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• Voluntary written consent (donor or parent/guardian for minors with assent) 
prior to any research related procedures 
5 
Study Registration  
Registration will occur after the patient and/or parent/guardian has signed the 
appropriate consent form and eligibility is confirmed, but before any study related 
procedures are performed.  To be eligible for registration to this study, the patient must 
meet each of the criteria listed on the eligibility checklist (appendix I, and if Arm B, 
appendix II) based on the eligibility assessment documented in the patient’s medical 
record.   
Upon completion of the screening evaluation, eligibility confirmation and obtaining 
written consent, the study coordinator or designee will register the patient in OnCore.   
At the time of registration, the patient will enrolled on one of the following study arms 
based on the epidermal cell source: 
Arm A:  Previous hematopoietic cell transplant (HCT) donor 
Arm B:  Patient (self-donation) 
Donors for patients enrolled on Arm A will meet each criteria listed on the donor 
eligibility checklist (appendix II) and be registered in OnCore per Masonic Cancer 
Center guidelines. 
6 
Treatment Procedures 
6.1 EB Wounds  
We will identify up to 3 regions indicated for grafting with an equal number of 
control (no treatment) lesions (as able).  Such wounds would be open erosions, 
apparently free of infection (as documented by physical exam—local redness, 
swelling, and pain—as microbiome is inevitable and physiologic on any muco-
cutaneous surface).  Whenever possible, we will seek symmetrical wounds 
(relative to median axis on the head and trunk, or relative to long axis on 
extremities) and plan to treat one side only in the first setting.  In this fashion we 
will be able to compare the dynamics of healing of untreated (“control”) and treated 
sites, while the systemic factors (such as, level of activity, inflammation, 
environmental influences) remain approximately the same.  If there are no 
significant side effects, we will treat the “control” wounds and/or other wounds after 
a minimum 12-week period of observation after the initial grafting, and in serial 

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fashion after that with up to three sessions anticipated over the approximately one-
year follow-up period from time of initial CelluTome session (refer to section 6.4). 
6.2 Healthy Skin Grafts   
We will identify optimal harvesting sites on the body of recipient. Although the 
epidermal collection is essentially painless (donor will feel warmth and mild 
pressure at the site) and leaves infrequent, mild scarring and/or hypopigmentation 
we will not choose intensely exposed locations, such as head, neck, palms and 
soles. The primary collection site is often the thigh, but as skin is developmentally, 
structurally and functionally different at different parts of the body we will attempt 
collection of epidermis from a general area on the recipient’s body that 
corresponds to the site of the wound being treated.  Of course, we are prepared to 
adapt to physical specifics and psychological choices of the recipient. For Arm B 
enrollees, grafts will be taken from sites without history of blistering. 
6.3 Epidermal Transfer 
The grafting will be done in real time.  This FDA approved (Regulation number 
878.4820) operating procedure will be followed in all details to collect the donor 
epidermis from a maximum of 3 sites at one sitting and to transfer it to up to 3 
regions in the recipient location.  Grafts will be secured with bandages and 
protected for at least 2 weeks, and preferably up to 3-4 weeks if possible. Patients 
are educated on how to re-apply grafts that have fallen off (i.e. cleanse with saline 
and re-apply if < 2 weeks and no obvious contaminate of the graft)., although it is 
not presumed to be detrimental if these grafts are not in place the full 2-4 weeks. 
Wounds will be observed for any signs of infection, photographed weekly (along 
with the respective “control” wounds) as able. 
 
6.4 Subsequent Wound Treatment 
It is recognized that most participants will have additional wounds (including the 
control lesions from the initial treatment event) which could benefit from healthy 
tissue grafting.  Patients will be offered treatment of up to 3 additional regions  if at 
least 12 weeks has passed since the last treatment, if there were no unacceptable 
outcomes from previous graft procedures and if the original donor is available.  
Subsequent treatments would not contribute to the primary and secondary study 
endpoints, but data will be collected in a similar fashion including weekly 
photographs (as able) for clinical care and follow-up of wound BSA with wound 
BSA analyzed ideally at 6 and 12 weeks (as well as additional follow-up timepoints 
for other treatment sessions/clinical care) for publication. 
 

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Patients who have additional wounds that could benefit from CelluTome after one 
year of treatment with no significant adverse events attributable to the CelluTome 
procedure will be offered to extend treatment and re-enroll for an additional year. 
Re-consent would then occur with each annual follow-up if the patient wishes to 
extend treatment with the intent of collecting data for publication; otherwise 
subsequent sessions could be completed off-protocol as compassionate care 
without data collection for publication. If additional wounds are treated the original 
schedule (i.e. 1 year follow-up) will be adhered to as the 1st set of treated/control 
wounds are for the study endpoints.  Subsequent wound treatment will be treated 
as an independent event (i.e. start as a new day 0) and the schedule in section 8 
will serve as a guideline, therefore deviations from this schedule for subsequent 
treatment sessions will not be considered protocol deviations.  Because 
subsequent treatments will not contribute to the study endpoints, follow-ups 
(weeks 6 and 12, at 1 year), may be performed remotely or at a medical facility 
closer to home with the results sent to our institution.  Although it is recommended 
the patient return for follow-up assessment at approximately 12 weeks and 1 year 
post initial grafting session, remote or local follow-up will be allowed.  
 
7 Expected Risks 
 
7.1 Donor  
We do not expect any significant side-effects as this procedure has been accepted 
as safe in the field and used for treatment of number of skin conditions, such as 
vitiligo and diabetic leg ulcers, with an excellent safety profile.16-19  Of note, though 
the harvested tissue (epidermis) does not cross the basement membrane, the 
procedure is essentially painless (donor will feel warmth and mild pressure at the 
site) and there is infrequent, mild scarring and/or hypopigmentation, we will still 
examine the sites of epidermal harvest via weekly photographs until healed (as 
able) and at  12 weeks as able for any abnormalities detectable by physical 
examination. 
7.2 Recipient 
Even though the graft and recipient are uniquely and fully HLA matched, there can 
be local (and much less likely systemic) effects of grafting.  Most prominent among 
these is non-engraftment (sloughing off the graft) because of subclinical infection, 
ongoing fibrosis and—related to that—inadequate vascular supply at the recipient 
site.  This can be accompanied by local inflammation with systemic febrile reaction, 
though none would be expected to be serious adverse events.  

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8 Schedule of Events 
8.1 Patient (Recipient – Arm A/re-enrollments Arm C) 
 
Prior to 
CelluTome 
Treatment 
Day Of 
Harvest 
(Day 0) 
Weekly 
Until 12 
Week Visit3 
6 
Weeks  
(+/- 1 
Week)5 
12 
Weeks 
(+/- 1 
Week)6 
1 Year (+/- 
3 Months) 6 
Written consent 
X 
 
 
 
 
 
Physical exam 
 
X 
 
X 
X 
X 
Identification by 
physical exam and 
documentation of EB 
wounds1 
 
X 
 
 
 
 
Donor chimerism 
X 7 
 
 
 
 
 
Photographs of the 
targeted lesions (and 
“control” lesions as 
able)  
X  
anytime between baseline and 
harvest  
 
X 
by parent or 
caretaker via 
iphone or 
similar device 
X 
X 
X 
Transfer of the 
epidermal micrografts 
from donor to the 
recipient sites 
 
X 
  
 
 
 
Assessment of 
adverse events 
 
X 
 
X 
X 
X 
Quality of life -  itch 
and pain scales, 
(iscorEB)2 
X 
 
X 
X 
X 
Research skin 
biopsies8 
X 
1 – a maximum of 3 EB regions  will be identified for treatment with additional wounds considered controls (as able).  
If there are no significant side effects, control wounds and/or other wounds may be treated after a minimum of 12 
weeks of  observation after the initial grafting per section 6.4.  
2 –testing/procedures may be waived, if performed recently as part of follow-up on an EB treatment protocol (i.e. 
MT2009-09 or MT2015-20) or as standard of care, if the results are available for this study. Will attempt collection of 
full iscorEB at annual visits in accordance with standard of care, but at minimum, patient portion is requested for 
analysis of pain and itch.  
3 – If possible 
4 – footnote deleted 
5 -May be conducted remotely through UMN provider or the patient’s home/local provider if physical assessment 
indicated and the patient is unable to return to UMN 
6- Ideally at UMN site unless patient is absolutely unable to return, in which case local or remote assessment should 
be completed with results sent to the PI and study staff 
7- Peripheral blood donor chimerism should be measured within 21 days of grafting and be >/= 5% and stable. 
Stability of chimerism will be determined by the protocol team and based on 3 peripheral blood chimerism values at 
least 1 month apart 
8 – Three 4mm punch biopsies (optional) at a grafted site to examine immunofluorescence, electron microscopy, and 
donor engraftment taken at time of routine sedated procedure during the 1-year follow-up time period.  
 
 

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8.2 Donor (Arm A) 
 
Prior To 
CelluTome 
Treatment 
Day Of 
Harvest 
(Day 0) 
Weekly Until 
The Week 12 
Visit1 
6 Weeks 
And 12 
Weeks 
(+/- 1 
Week)2 
1 Year (+/- 
3 Months)2 
Written consent 
X 
 
 
 
 
Brief assessment 
X 
 
 
X 
X 
Donor infectious disease 
panel 
X3 
 
 
 
 
Identification and 
documentation of harvesting 
sites (maximum of 3 sites)  
 
X 
 
 
 
Epidermal harvesting  
 
X 
 
 
 
Photographs of harvest 
sites  
 
X (pre) 
X 
 by parent or 
caretaker via 
iphone or similar 
device 
X 
 
Assessment of adverse 
events 
 
X 
 
X 
X 
1 – if possible; not needed once harvest site is healed per PI.  
2 - Donors may be assessed remotely if unable to return to primary site 
3 - Within 30 days of harvest 
 
8.3 Patient (Self Donor – Arm B/re-enrollments Arm D) 
 
Prior To 
CelluTome 
Treatment 
Day Of 
Harvest 
(Day 0) 
Weekly 
Until The 
Week 12 
Visit3 
6 
Weeks 
And 
(+/- 1 
Week)5 
12 
Weeks 
(+/- 1 
Week)6 
1 Year 
(+/- 3 
Months)6 
Written consent 
X 
 
 
 
 
 
Physical exam 
 
 
 
X 
X 
X 
Identification by physical 
exam and documentation 
of EB wounds1 
 
X 
 
 
 
 
Baseline skin biopsy of 
unaffected (possibly 
revertent or mosaic) site 
and affected site to 
confirm somatic 
reversion2 
X 
 
 
 
 
 
Identification and 
documentation of 
harvesting sites  
X 
 
 
 
 
 
Photographs of the 
targeted lesions, (“control” 
lesions, and harvest sites 
as able) 
X 
 
anytime between baseline and 
harvest  
X 
by parent or 
caretaker via 
iphone or 
similar device 
X 
X 
X 

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Prior To 
CelluTome 
Treatment 
Day Of 
Harvest 
(Day 0) 
Weekly 
Until The 
Week 12 
Visit3 
6 
Weeks 
And 
(+/- 1 
Week)5 
12 
Weeks 
(+/- 1 
Week)6 
1 Year 
(+/- 3 
Months)6 
Epidermal harvest and 
transfer of the epidermal 
micrografts to the targeted 
lesions 
 
X 
 
 
 
 
Assessment of adverse 
events 
 
X 
 
X 
X 
X 
Quality of life , itch and 
pain scales (iscorEB)2 
X  
anytime between baseline and 
harvest  
 
X 
X 
X 
Research skin biopsies7 
X 
1 – a maximum of 3 EB regions will be identified for treatment with additional wounds considered controls 
(as able).  If there are no significant side effects, control wounds and/or other wounds may be treated 
after a minimum of 12 weeks of observation after the initial grafting per section 6.4. 
2 –testing/procedures may be waived, if performed recently as part of follow-up on an EB treatment protocol (i.e. 
MT2009-09 or MT2015-20) or as standard of care, if the results are available for this study. Will attempt collection of 
full iscorEB at annual visits in accordance with standard of care, but at minimum, patient portion is requested for 
analysis of pain and itch.  
3– If possible 
4 – footnote deleted 
5 - May be conducted remotely through UMN provider or the patient’s home/local provider if physical assessment 
indicated and the patient is unable to return to UMN 
6-  Ideally at UMN site unless patient is absolutely unable to return, in which case local assessment should be 
completed with results sent to the PI and study staff 
7 – Two 4mm punch biopsies (optional) at a grafted site to examine immunofluorescence, electron microscopy, at 
time of routine sedated procedure during the 1-year follow-up time period.  
9 Adverse Event Monitoring, Recording and Reporting 
Toxicity and adverse events will be classified according to NCI's Common Terminology 
Criteria for Adverse Events V 4.0 (CTCAE) and reported on the schedule below. A copy 
of 
the 
CTCAE 
events 
can 
be 
downloaded 
from 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40  
9.1 Event Monitoring/Documentation of Donor Sites and Recipient Sites 
Event monitoring will focus on: 1) the areas from which the skin cells are 
harvested and 2) the sites to which the skin cells are applied for signs of poor 
healing (inflammation, sloughing of skin) with or without systemic fever.   
 
Any adverse event, CTCAE v 4 ≥ grade 3 and felt to be at least possibly related 
to the epidermal grafting procedure will be documented in OnCore.  The trial will 
halt enrollment and be re-evaluated if a grade 4 (CTCAE v4) skin related event 
occurs in any one of the treated lesions per section 12.4 and is at least possibly 
related to the epidermal grafting procedure. 

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9.2 Event Reporting 
Certain events, in addition to recording on the study’s eCRF’s, will require prompt 
reporting to the University of Minnesota according to the table below: 
10 Data Collection and Study Monitoring 
10.1 Data Management 
This study will report clinical data using The Online Enterprise Research 
Management Environment (OnCoreTM), a web based Oracle® database utilizing 
study specific electronic case report forms.  Key study personnel will be trained on 
the use of OnCore and will comply with protocol specific instructions embedded 
within the OnCore forms.  Patient demographics, patient specific study treatment 
calendars, adverse events, reporting of deaths, and other information will be 
placed in OnCore. The iScorEB results will be recorded in the BMT database.  All 
biopsy results and photographs will be maintained and stored under the 
supervision of the PI.  
10.2 Case Report Forms 
Participant data will be collected using protocol specific electronic case report 
forms (e-CRFs) developed within OnCore based on its library of standardized 
forms.  The e-CRF will be approved by the study’s Principal Investigator and the 
Biostatistician prior to release for use.   
10.3 Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan 
(DSMP), which can be accessed at https://z.umn.edu/dsmp  
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
information 
Copy to: 
U of MN IRB 
Events requiring prompt reporting 
including, but not limited to 
unanticipated death of a locally enrolled 
subject(s); any unanticipated adverse 
device effect, new or increased risk; 
any adverse event  that require a 
change to the protocol or consent form 
or any protocol deviation that resulting 
in harm refer to  
http://www.research.umn.edu/irb/forms.
html 
within 5 
business 
days of 
discovery 
Report 
Form 
irb@ 
umn.edu 
SAE 
Coordinator 
mcc-
saes@umn.
edu 

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For the purposes of data and safety monitoring, this study is classified as moderate 
risk.  Therefore the following requirements will be fulfilled: 
 The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will 
review the trial’s progress twice yearly. 
 The PI will comply with at least twice yearly monitoring of the clinical protocol 
by the Masonic Cancer Center monitoring services.   
 The PI will oversee the submission of all reportable adverse events per the 
definition of reportable in section 9.2 to the Masonic Cancer Center’s SAE 
Coordinator and the University of Minnesota IRB.   
 
In addition, at the time of the continuing review with the University of Minnesota 
IRB, a copy of the report with any attachments will be submitted to the Cancer 
Protocol Review Committee (CPRC). 
11 Outcome Measures 
Multiple wounds may be treated for each patient.  The primary outcome measure is the 
percentage of grafts successfully treated.  Therefore, the experimental unit for this pilot 
study will be the wound, not the patient.  If the body surface area affected by the wound 
is at least 50% lower at 12 weeks relative to baseline, the graft will be considered 
successful.  For the purposes of this study only the initial treatment session (of up to 3 
wounds for treatment and an equal number of control wounds) will be used for fulfilling 
the primary and secondary study endpoints. 
 
Healing of wounded skin is a fairly stereotypic process in simple wounds, but becomes 
complicated and complex in the setting of multiple factors converging on the status of a 
wound at specific time.  This includes: type of EB, gene mutation causing the RDEB or 
JEB, polymorphisms in modifier genes (such as enzymes that recycle skin extracellular 
matrix), infection and inflammation (local and systemic), HCT factors (age, graft, type of 
conditioning, physical and immune complications), and resulting hematopoietic and skin 
chimerism. 20-24   
 
Therefore, we will use several measures in the recipient (the patient with EB) to establish 
a template for the most accurate and unbiased evaluation of benefits associated with 
epidermal grafting, as follows: 
 
[1] Physical exam. Comprehensive evaluation will be performed at 0 (i.e., before) 
grafting, at 6 (remote visit via phone assessment possible if physician and family agree 
travel to U of MN not clinically indicated) and 12 weeks, and 1 year after grafting. 
 

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[2] Photographs. In addition to photographs taken with an iPad or similar device, a 
specialized camera or photograph with standard measuring device in picture  may be 
used at these four time-points (0, 6 and 12 weeks and 1 year after grafting) per PI 
discretion to allow for quantitative assessment of wound size over time. Weekly 
photographs will also be requested as able until the week 12 visit to assess healing and 
for any adverse events.  
  
[3] iscorEB. A validated, EB-specific scale used to capture data regarding quality of life, 
pain and itching will be obtained at 0, 6 and 12 weeks and 1 year after grafting. 20,23,24 
 
[4] Donor assessments. Follow up physical assessments, adverse event assessments, 
and photos can be performed remotely at donor’s home clinic (if physical exam is 
clinically indicated) or with UMN physician (i.e. telephone call, skype, etc.), if donor is 
not able to return. 
 
Of note, all these procedures are fully operational and have been used extensively to 
assess clinically relevant and actionable data in more than 50 individuals from families 
with RDEB and JEB evaluated at the UMN over last 8 years. As we have established 
immune tolerance after successful grafting of bone marrow or umbilical cord blood, we 
have been developing approaches to leverage this immune tolerance in local therapy. 
We plan to use Cellutome® as a complementary therapeutic measure for difficult to heal 
erosions after hematopoietic cell transplantation (Arm A) or in autologous setting for 
transfer of mosaic skin (Arm B).  As the immune system of the recipient will "see" such 
skin grafts as "self" this is an elegant way of clinical application of acquired immune 
tolerance in transplantation biology. 
 
12 Statistical Considerations 
This is a pilot study with the purpose of determining preliminary efficacy and safety 
measures of epidermal skin grafting in EB patients.  Arm A (graft from hematopoietic stem 
cell donor) and Arm B (self-donor) will be analyzed separately.  
After 1 year on study, patients may re-enroll on the trial. These will be considered new 
subjects (each enrollment counts separately). Allogeneic recipient re-enrollments will be 
considered Arm C (treatment plan identical to Arm A) and self recipient re-enrollments 
will be considered Arm D (treatment plan identical to Arm B). Arm C and Arm D will not 
contribute to primary or secondary outcomes, but a descriptive summary of Arms C and 
D will be performed separately. 

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12.1 Trial Size 
Target accrual is 25 patients on arm A and 10 subjects on arm B over three years.  
Analysis of the primary endpoint can occur 12 weeks after the last subject begins 
treatment.  Some secondary safety endpoints will be collected for 1 year. 
 
Up to additional 25 patients may re-enroll in the study – these patients count toward 
a total study enrollment goal of 60 but only the initial enrollments will contribute to 
primary and secondary outcomes. 
12.2 Analysis of Primary Endpoint 
Each wound will be photographed before treatment, and at 6 and 12 weeks after 
treatment.  If the body surface area affected by the wound is at least 50% lower at 
12 weeks relative to baseline, the graft will be considered successful.  The primary 
outcome measure is the percentage of grafts successfully treated as evaluated by 
a “blinded” reviewer. 
 
Multiple wounds may be treated for each patient.  The degree of correlation in 
response is unknown, but we expect that different wounds on the same patient 
could respond differently.  Therefore, the experimental unit for this pilot study will 
be the wound, not the patient.  If a mean of 2 wounds are treated for each enrolled 
patient, the 95% confidence interval of the response proportion will be as follows: 
 
 
Observed  
response 
95% CI in Arm A 
(50 lesions) 
95% CI in Arm B 
(20 lesions) 
25% 
(14%, 39%) 
(9%, 49%) 
50% 
(36%, 64%) 
(27%, 73%) 
75% 
(61%, 86%) 
(51%, 91%) 
90% 
(78%, 97%) 
(68%, 99%) 
12.3 Analysis of Secondary Endpoints 
The iscorEB (which includes measures of quality of life questionnaire, pain and 
itching) will be summarized by means and standard deviations.  Changes over time 
will be compared using Wilcoxon signed-rank tests.  
12.4 Safety Monitoring 
The trial will halt enrollment and be re-evaluated if a grade 4 (CTCAE v4) or higher 
skin related event at least possibly related to the CelluTome device or skin 
transplant procedures occurs in any one of the treated lesions. 

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13 Ethical and Regulatory Considerations 
13.1 Conduct of the Study 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s).  Essential clinical documents will be maintained to demonstrate 
the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the 
study and retained according to the appropriate regulations.   
13.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki.  The IRB will review all appropriate study documentation 
in order to safeguard the rights, safety and well-being of the participants.  The 
study will only be conducted after IRB approval has been obtained.  The protocol, 
written consent document, safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB by the investigator.   
13.3 Informed Consent  
All potential study participants will be given a copy of the IRB-approved consent (if 
minor - parents/guardians with minor assent) to review.  The investigator or 
designee will explain all aspects of the study in lay language and answer all 
questions regarding the study.  If the decision is made to participate in the study, 
the appropriate consent documents will be signed.  Participants who refuse to 
participate or who withdraw from the study will be treated without prejudice. 
14 References 
1. Bruckner-Tuderman L. Dystrophic epidermolysis bullosa: pathogenesis and clinical features. 
Dermatol Clin 2010; 28(1): 107-14. 
2. Fine JD, Eady RA, Bauer EA, et al. The classification of inherited epidermolysis bullosa (EB): 
Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. 
J Am Acad Dermatol 2008; 58(6): 931-50. 
3. Uitto J, McGrath JA, Rodeck U, Bruckner-Tuderman L, Robinson EC. Progress in 
epidermolysis bullosa research: toward treatment and cure. J Invest Dermatol 2010; 130(7): 
1778-84. 
4. Wong T, Gammon L, Liu L, et al. Potential of fibroblast cell therapy for recessive dystrophic 
epidermolysis bullosa. J Invest Dermatol 2008; 128(9): 2179-89. 
5. Kern JS, Loeckermann S, Fritsch A, et al. Mechanisms of fibroblast cell therapy for dystrophic 
epidermolysis bullosa: high stability of collagen VII favors long-term skin integrity. Mol Ther 
2009; 17(9): 1605-15. 
6. Conget P, Rodriguez F, Kramer S, et al. Replenishment of type VII collagen and re-
epithelialization of chronically ulcerated skin after intradermal administration of allogeneic 

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mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa. 
Cytotherapy 2010; 12(3): 429-31. 
7. Ortiz-Urda S, Lin Q, Green CL, Keene DR, Marinkovich MP, Khavari PA. Injection of 
genetically engineered fibroblasts corrects regenerated human epidermolysis bullosa skin 
tissue. J Clin Invest 2003; 111(2): 251-5. 
8. Titeux M, Pendaries V, Hovnanian A. Gene therapy for recessive dystrophic epidermolysis 
bullosa. Dermatol Clin 2010; 28(2): 361-6, xii. 
9. Titeux M, Pendaries V, Zanta-Boussif MA, et al. SIN Retroviral Vectors Expressing COL7A1 
Under Human Promoters for Ex Vivo Gene Therapy of Recessive Dystrophic Epidermolysis 
Bullosa. Mol Ther 2010. 
10. Woodley DT, Keene DR, Atha T, et al. Intradermal injection of lentiviral vectors corrects 
regenerated human dystrophic epidermolysis bullosa skin tissue in vivo. Mol Ther 2004; 10(2): 
318-26. 
11. Remington J, Wang X, Hou Y, et al. Injection of recombinant human type VII collagen corrects 
the disease phenotype in a murine model of dystrophic epidermolysis bullosa. Mol Ther 2009; 
17(1): 26-33. 
12. Woodley DT, Remington J, Huang Y, et al. Intravenously injected human fibroblasts home to 
skin wounds, deliver type VII collagen, and promote wound healing. Mol Ther 2007; 15(3): 
628-35. 
13. Yasuda M, Claypool DJ, Guevara E, Roop DR, Chen J. Genetic manipulation of keratinocyte 
stem cells with lentiviral vectors. Methods in molecular biology 2013; 989: 143-51. 
14. Chen M, Kasahara N, Keene DR, et al. Restoration of type VII collagen expression and 
function in dystrophic epidermolysis bullosa. Nat Genet 2002; 32(4): 670-5. 
15. De Luca M, Pellegrini G, Mavilio F. Gene therapy of inherited skin adhesion disorders: a 
critical overview. Br J Dermatol 2009; 161(1): 19-24. 
16. Osborne SN, Schmidt MA, Derrick K, Harper JR. Epidermal micrografts produced via an 
automated and minimally invasive tool form at the dermal/epidermal junction and contain 
proliferative cells that secrete wound healing growth factors. Adv Skin Wound Care. 2015 
Sep;28(9):397-405. 
17. Howarth AL, Bell BE, Peterson WC, Renz EM, King BT, Chan RK.  A novel approach to graft 
loss in burn using the CelluTome™ epidermal harvesting system for spot grafting: a case 
report.  Burns. 2015 Sep;41(6):e57-60. 
18. Serena TE. Use of epidermal grafts in wounds: a review of an automated epidermal harvesting 
system.  J Wound Care. 2015 Apr;24(4 Suppl):30-4.  
19. Serena T, Francius A, Taylor C, MacDonald J.  Use of a novel epidermal harvesting system 
in resource-poor countries.  Adv Skin Wound Care. 2015 Mar;28(3):107-12.  
20. Schwieger-Briel A, Chakkittakandiyil A, Lara-Corrales I, Aujla N, Lane AT, Lucky AW, 
Bruckner AL, Pope E.  Instrument for scoring clinical outcome of research 
for epidermolysis bullosa: a consensus-generated clinical research tool.  Pediatr Dermatol. 
2015 Jan-Feb;32(1):41-52. doi: 10.1111/pde.12317. Epub 2014 Mar 20. 
21. Mack MR, Wendelschafer-Crabb G, McAdams BD, Hordinsky MK, Kennedy WR, Tolar J.  
Peripheral neuro-immune pathology in recessive dystrophic epidermolysis bullosa.  J Invest 
Dermatol. 2015 Apr;135(4):1193-7. doi: 10.1038/jid.2014.500. Epub 2014 Nov 14. 

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22. Petrof G, Lwin SM, Martinez-Queipo M, et al.  Potential of Systemic Allogeneic Mesenchymal 
Stromal Cell Therapy for Children with Recessive Dystrophic Epidermolysis Bullosa.  J Invest 
Dermatol. 2015 Sep;135(9):2319-21. doi: 10.1038/jid.2015.158. Epub 2015 Apr 23. 
23. Fine JD, Johnson LB, Weiner M, Suchindran C.  Assessment of mobility, activities and pain in 
different subtypes of epidermolysis bullosa.  Clin Exp Dermatol. 2004 Mar;29(2):122-7. 
24. Snauwaert JJ, Yuen WY, Jonkman MF, Moons P, Naulaers G, Morren MA.  Burden of itch in 
epidermolysis bullosa.  Br J Dermatol. 2014 Jul;171(1):73-8. doi: 10.1111/bjd.12885. Epub 
2014 Jun 22. 
 
 

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Appendix I – Eligibility Checklist – Patient/Recipient 
Study of Epidermal Grafting Using the CelluTome® Epidermal Harvesting System 
for the Treatment of Individual Lesions in Persons with Epidermolysis Bullosa  
Eligibility Checklist – page 1 of 1 
Participant initials   
      
Patient ID   
  (assigned in OnCore) 
 
INCLUSION CRITERIA  
A “NO” response to any of the following disqualifies the participant from study entry. 
 
 
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify that this 
participant is eligible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of enrolling researcher 
 
 
 
 
 
Date 
 
 
Yes      No 
1 
Diagnosis of Dystrophic Epidermolysis Bullosa (RDEB) or Junctional 
Epidermolysis Bullosa (JEB) with at least one  wound, visibly free from infection 
and meets the eligibility for Arm A or Arm B 
 
 
2 
  Cell harvest from  previous HCT donor (Arm A) – meets all of the following: 
- At least 6 months  after HCT with donor hematopoietic chimerism  
- Peripheral blood donor chimerism should be measured within 21 days of 
grafting and be >/= 5% and stable. Stability of chimerism will be determined 
by the protocol team and based on 3 peripheral blood chimerism values at 
least 1 month apart off immune suppressive therapy 
- Original transplant donor is available and willing to be the epidermis donor 
 
 
or check if 
not 
applicable   
 
3 
   Self-donation (Arm B) – meets all of the following: 
- Proven somatic reversion  
- Site for skin grafting free of cellulitis and any other clinically evident 
abnormalities 
- Meets eligibility for Donor (appendix II) 
 
 
or check if 
not 
applicable  
 
4 
Insurance pre-authorization for procedure 
 
 
or check if 
not 
applicable  
 
5 
Voluntary written appropriate consent (Arm A patient or Arm B) 
 
 

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Appendix II – Eligibility Checklist – Donor 
Study of Epidermal Grafting Using the CelluTome® Epidermal Harvesting System 
for the Treatment of Individual Lesions in Persons with Epidermolysis Bullosa  
Eligibility Checklist – page 1 of 1 
 
 
Donor initials   
     
 
Patient ID   
  (assigned in OnCore) 
 
INCLUSION CRITERIA  
A “NO” response to any of the following disqualifies the participant from study entry. 
 
 
 
 
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify that this 
donor is eligible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of enrolling researcher 
 
 
 
 
 
Date 
 
 
 
 
 
 
Yes      No 
1 
Age > 2 years (based on prior safety testing of the device) 
 
 
2 
Healthy on physical examination in the opinion of the evaluating provider 
 
 
4 
Negativity for Hepatitis B and C, HIV, and HTLV1/2 within 30 days of donation 
 
 
5 
Voluntary written consent (donor or parent/guardian for minors) prior to any 
study related procedures (Arm A donor)   
Note:  Patients enrolling on Arm B (Non-HCT autologous recipient), the Arm B 
consent form covers both donor and recipient information in a single document 
 
 
 

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Appendix III – CelluTome Procedure Overview 
Note:  It is recognized in this CelluTome Procedure Overview that an adhesive dressing, 
Tegaderm® is used; however in this study a non-adhesive silicone mesh dressing is used and 
referenced as such through the protocol document. 
 
 
 
 

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