EDITORIAL

RDEB: regeneration is not enough

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is an
inherited blistering skin disease characterized at molecular
level by mutations of the COL7A1 gene which encodes for
type VII collagen. Type VII collagen is an integral part of the
dermo-epidermal junction that has been well characterized
by Burgeson and Christiano.
1
The clinical severity of the
condition will depend on the mutation present and Dong and
Murrel have reported more than 320 pathogenic mutations
2
and Woodley et al have characterized the molecular
mechanisms underlying the mutations.
3
The spectrum of
disease is very wide ranging from minor dystrophy in the
nails to the more severe forms where there is a signicant
fragility of the skin with recurrent wounds, infection,
scarring, deformity, failure to thrive and premature death
from squamous cell carcinoma.
4
Although there are many
supportive managements to ameliorate the effects of the
disease, there is currently no treatment for the underlying
cause; defective and decient type VII collagen.
The main treatment strategies have focused on the
replacement of the abnormal collagen VII using genetic,
cell or protein based approaches. Mavilio et al have used
genetically modied epidermal stem cells to treat junc-
tional epidermolysis bullosa.
5
A tissue engineered construct
comprising a broblast-populated collagen gel on which
a stratied keratinized layer of epidermal cells has been
grown has been reported to accelerate and maintain the
healing of wounds in RDEB. The allogeneic cells are derived
from cultures of neonatal foreskin and are of reduced
immunogenicity due to their serial passaging in culture.
6
Cell based strategies have focused primarily on dermal
broblasts. This has been based on gene-transfection
studies using skin grafts to nude mice which revealed the
gene transferred broblasts supplied higher amounts of
collagen VII to the newly formed DEJ than gene-transferred
keratinocytes.
7
This was a very important observation as
previously it had been thought that in vivo most type VII
collagen comes from the keratinocytes. As Chen and
Woodley discuss in the commentary to Goto et als paper,
the broblast is a much easier cell to work with than the
keratinocyte and is much less susceptible to growth arrest
and differentiation. Indeed as broblasts can be passaged
20e30 times in vitro a single, genetically modied
broblast can be expanded to greater than 10
20
cells.
8
A
recent clinical study looking a intradermal injections of
allogenic broblasts in six patients with RDEB indicated
a positive response. This response was better in the least
severe clinical forms and appeared to be related to a stim-
ulation of autologous collagen VII production.
9,10
The roles of the keratinocyte and broblast in the
formation of the DEJ have been investigated in an in vitro
model of the broblast populated collagen lattices onto
which keratinocytes are seeded. The model is allowed to
developed at the air liquid interface to allow keratinocyte
stratication.
11
Animal models for RDEB have been prob-
lematic as knock out mice with absent Collagen VII cannot
survive. Targeted inactivation has been attempted but it is
the hypomorphic mouse model which holds the greatest
promise for long term in vivo recovery experiments.
12e14
The hypomorphic mouse model has been developed
by Professor Leena Bruckner-Tudermans group in the
Department of Dermatology at the University of Freiburg.
This is the transgenic EB mouse model Col7a1
Neo/Neo
. This
is an immunocompetent animal model for dystrophic EB
(DEB). These mice express collagen VII at about 10% of
normal levels and their phenotype closely resembled
characteristics of severe human DEB, including mucocuta-
neous blistering, nail dystrophy, and mitten deformities of
the extremities. The advantages of this model is that the
pathology is caused by a reduced level of normal collagen
VII, but not by interference of mutated molecules which
would generate a variety of abnormal structures leading to
high mortality rate at birth. The Col7a1
Neo/Neo
mice
survive to adulthood; it makes this model ideally suited for
evaluation of novel therapeutic strategies.
The severe forms of RDEB are devastating in their impact
on the lives of the patient and extremely challenging to
manage. A recent experience with a patient referred with
a circumferential forearm SCC (Figure 1) underlined this chal-
lenge in terms of anaesthesia, patient handling as well as
reconstructive strategies. The use of Integra, and mixed auto-
genic meshgraft andallogenickeratinocytespray(Figure2) has
achieved an effective cover but for how long (Figure 3)?
Earlier this year I discussed the new logo of BAPRAS e
the salamander and described it as an inspired choice for
1748-6815/$ - see front matter 2008 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.
doi:10.1016/j.bjps.2008.10.008
Journal of Plastic, Reconstructive & Aesthetic Surgery (2008) 61, 1421e1422
reconstructive surgeons.
15
Briey e the salamander is of
the order Urodele e the only adult vertebrates capable of
regeneration. Regeneration is the goal of all Plastic
Surgeons. Or is it? My patient with severe RDEB does not
want simple regeneration. He has a genetic abnormality
and imperfectly provides collagen VII to the dermo-
epidermal junction. He does not want more of the same he
wants some thing more than regeneration. He wants,
needs, regeneration plus a new gene. There is no doubt
that this is going to happen, not tomorrow but some time in
the future. And looking at that future it is evident that
there will be an ever increasing interaction between
surgeons and scientists. A partnership that needs planning,
preparation and support as we train surgeons for the future.
References
1. Burgeson RE, Christiano AM. The dermal-epidermal junction.
Curr Opin Cell Biol 1997;9:651e658.
2. Dang N, Murrell DF. Mutation analysis and characterization of
COL7A1 mutations in dystrophic epidermolysis bullosa. Exp
Dermatol 2008;17:553e568.
3. Woodley DT, Hou Y, Martin S, et al. Characterization of
molecular mechanisms underlying mutations in dystrophic
epidermolysis bullosa using site-directed mutagenesis. J Biol
Chem 2008;283:17838e17845.
4. Mallipeddi R. Epidermolysis bullosa and cancer. Clin Exp Der-
matol 2002;27:616e623.
5. Mavilio F, Pellegrini G, Ferrari S, et al. Correction of junctional
epidermolysis bullosa by transplantation of genetically modi-
ed epidermal stem cells. Nat Med 2006;12:1397e1402.
6. Falabella AF, Valencia IC, Eaglstein WH, et al. Tissue-engineered
skin (Apligraf) in the healing of patients with epidermolysis
bullosa wounds. Arch Dermatol 2000;136:1225e1230.
7. GotoM, SawamuraD, ItoK, et al. Fibroblasts showmorepotential as
target cells than keratinocytes in COL7A1 gene therapy of dystro-
phic epidermolysis bullosa. J Invest Dermatol 2006;126:766e772.
8. Chen M, Woodley DT. Fibroblasts as target cells for DEB gene
therapy. J Invest Dermatol 2006;126:708e710.
9. Wong T, Gammon L, Liu L, et al. Potential of broblast cell
therapy for recessive dystrophic epidermolysis bullosa. J Invest
Dermatol 2008;128:2179e2189.
10. Uitto J. Epidermolysis bullosa: prospects for cell-based thera-
pies. J Invest Dermatol 2008;128:2140e2142.
11. Marionnet C, Pierrard C, Vioux-Chagnoleau C, et al. Interac-
tions between broblasts and keratinocytes in morphogenesis
of dermal epidermal junction in a model of reconstructed skin.
J Invest Dermatol 2006;126:971e979.
12. Jiang QJ, UittoJ. Animal models of epidermolysis bullosaetargets
for gene therapy. J Invest Dermatol 2005;124:xiexiii.
13. Heinonen S, Mannikko M, Klement JF, et al. Targeted inacti-
vation of the type VII collagen gene (Col7a1) in mice results in
severe blistering phenotype: a model for recessive dystrophic
epidermolysis bullosa. J Cell Sci 1999;112:3641e3648.
14. Fritsch A, Loeckermann S, Kern JS, et al. A hypomorphic mouse
model of dystrophic epidermolysis bullosa reveals mechanisms
of disease and response to broblast therapy. J Clin Invest
2008;118:1669e1679.
15. Burd A. Salamanders, lizards and ubiquitous stem cells. J Plast
Reconstr Aesthet Surg 2008;61:121e123.
Andrew Burd,
Editor, JPRAS,
Hong Kong
E-mail address: andrewburd@surgery.cuhk.edu.hk
Figure 1 Removing the SCC.
Figure 2 Second stage Integra with allogenic cell spray.
Figure 3 Fully healed.
1422 Editorial