IPCC NEWS BRIEF
by Emily Warshauer MD
University of Colorado
According to the Jedi master Obi-
Wan Kenobi in the Star Wars uni-
verse, “The Force is what gives a
Jedi his power. It’s an energy field
created by all living things…”
Unifying forces provide a founda-
tion that enables any system to
function effectively. The keratin
network too derives strength and
stability from an impressive set of
powerful forces that have still yet
to be completely understood.
In the recent December 2015 pub-
lication of the Journal of Cell Sci-
ence, Almeda and colleagues
acknowledged the complexity of
forces involved in the control of
the keratin network organization.
They recognized that the large cy-
toskeletal linker protein, plectin, is
an essential regulator of nuclear
morphology and protects the nu-
cleus from mechanical defor-
mation. The role of biophysical
forces underlying the crosstalk be-
tween plectin and the nucleus has
clearly been established, however
the precise mechanism remains a
mystery. Utilizing micro-
patterned collagen substrates to
manipulate cell shape, the authors
identified that disruption of the
keratin cytoskeleton through a loss
of plectin facilitated greater nucle-
ar deformation via reduced keratin
filament density around the nucle-
us.
Plectin constitutes such an im-
portant mediator of forces in the
maintenance of the substantial ker-
atin network that a loss of plectin
disrupts the keratin cytoskeleton so
detrimentally, resulting in severe
forms of Epidermolysis Bullosa
Simplex (EBS): EBS with muscu-
lar dystrophy, EBS with pyloric
atresia and EBS-Ogna. In the epi-
dermis of plectin-deficient epider-
molysis bullosa simplex patients,
keratinocytes were shown to have
abnormal nuclear morphologies.
Delving further into the versatility
of plectin, in the October 2015
publication of the Journal of Cell
Science, Nahidiazar and colleagues
utilized super-resolution microsco-
py to investigate additional keratin
connections with plectin. Notably,
they identified that plectin, in its
role as a hemidesmosomal plaque
protein, interacts in a simultaneous
and asymmetric fashion with beta-
4 integrin and keratin filaments.
This novel finding highlights intri-
cate forces at work between kera-
tin filaments and plectin in the as-
sembly of hemidesmosomes.
Deciphering the elaborate details
of the keratin network has long
been an ongoing effort. In April
2001 in the Journal of Investiga-
tive Dermatology, Sprecher and
colleagues performed structural
analyses and identified that a se-
vere form of epidermal hyperkera-
tosis (ichthyosis hystrix Curth-
Macklin) resulted from a unique
mutation in the variable tail do-
main of Keratin 1 (KRT1). This
defect was associated with a lack
of keratin bundling and retraction
of the cytoskeleton from the nucle-
us, directly impacting nuclear
shape. Might plectin have also
played a role?
In conclusion, the linker protein
plectin is clearly an important fig-
ure in the complex forces at play
to maintain keratin stability. Just
as Obi-Wan Kenobi was noble and
gifted, so too is plectin in the ways
of “the force” that it exerts to
maintain the keratin network.
References
Almeida F, Walko G, McMillan J,
McGrath J, Wiche G, Barber A,
Connelly J. The cytolinker plectin
regulates nuclear
mechanotransduction in
keratinocytes. J Cell Sci 2015.
Dec 15.
Nahidiazar L, Kreft M, van den
Broek B, Secades P, Manders EM,
Sonnenberg A, Jalink K. The
molecular architecture of
hemidesmosomes, as revealed with
2386 East Heritage Way, Ste B, Salt Lake City, UT 84109 · www.pachyonychia.org · Phone 877-628-7300 · Email: [email protected]
Vol 13, No. 1 Jan-Feb-Mar 2016
MAY THE
FORCE
BE WITH
KERATINS
2386 East Heritage Way, Ste B, Salt Lake City, UT 84109 · www.pachyonychia.org · Phone 877-628-7300 · Email: [email protected]
Page 2 IPCC News Brief Jan-Feb-Mar 2016 Vol 13, No 1
super-resolution microscopy. J
Cell Sci. 2015 Oct 15.
Natsuga K. Plectin-related skin
diseases. J Dermatol Sci. 2015
Mar.
Sprecher E. Evidence for Novel
Functions of the Keratin Tail
Emerging From a Mutation
Causing Ichthyosis Hystrix. J
Invest Dermatol. 2001 April.
THE VALUE AND NECESSITY
OF GENETIC TESTING Frances Smith, Chief Scientific
Officer, PC Project
The International Pachyonychia
Congentia Project Research Regis-
try (IPCRR) established in 2004,
has collected clinical and molecu-
lar data from nearly 700 PC pa-
tients. All are caused by a hetero-
zygous mutation in KRT6A,
KRT6B, KRT6C, KRT16 or
KRT17, and occur either as sponta-
neous cases or with known autoso-
mal dominant inheritance. Addi-
tionally, in the literature, all other
cases of PC with genetic testing
are also autosomal dominant.
However, a couple of early papers
report recessive PC, based on clin-
ical diagnosis with no genetic test-
ing. One paper quoted many times
over the years is 'Autosomal reces-
sive pachyonychia congeni-
ta' (Haber RM, Rose TH. Arch
Dermatol. 1986;122:919-23). Pub-
lished in 1986, this clinical diagno-
sis was prior to the identification
of PC keratin gene mutations. We
now know this is not recessive PC
but another rare skin disorder. Last
year (as reported in a previous
IPCC NewsBrief) a mutation was
identified in this family in the
CAST gene that causes PLACK
syndrome (Lin et al., Loss-of-
function mutations in CAST cause
peeling skin, leukonychia, acral
punctate keratoses, cheilitis, and
knuckle pads. Am J Hum Genet.
2015;96:440-7).
To avoid further misquoting of
recessive PC, Haber and Rose
have recently published a paper, to
correct their previous diagnosis
made in 1986 (before PC genes
were know), 'Identification of a
CAST mutation in a cohort previ-
ously misdiagnosed as having au-
tosomal recessive pachyonychia
congenita'. (Haber RM, Rose TH.
JAMA Dermatol. 2015;151:1393-
1394). They stress the importance
of genetic analysis to confirm a
clinical diagnosis, adding that
along with Clouston syndrome,
and others, PLACK syndrome is
another genodermatosis that may
mimic PC.
To date, all genetically confirmed
cases of PC show autosomal domi-
nant inheritance. There are no
known cases of autosomal reces-
sive PC confirmed by genetic anal-
ysis.
Clinical case reports are still pub-
lished as PC without genetic test-
ing, many of which, from the clini-
cal description do not appear typi-
cal of PC. For example, character-
istics such as baldness, deafness or
other features which are not asso-
ciated with PC are identified in
these so-called ‘novel’ cases of PC
with no genetic basis. This can be
confusing for both physicians and
PC patients. A correct diagnosis is
important for patient care and ge-
netic counselling. Genetic testing
is available at no charge to patients
and physicians through the IPCRR
to provide a correct diagnosis and
avoid further misinformation in the
literature.
For patients registered with the
IPCRR:
(1) genetic testing for the PC kera-
tin genes is FREE
(2) Testing is done using a saliva
kit provided by PC Project (no
blood draw) and easy to ship sam-
ple in the regular mail
(3) best benefits for physician, pa-
tient and family is to participate in
the registry
PC Project is careful to work with
referring physicians on publica-
tions resulting from the testing and
provide many support services to
the patient and family. Please refer
your patients and let your col-
leagues know of this free service.
PC PROJECT AWARDED
GLOBAL GENES GRANT We are pleased to announce that
PC Project was awarded a Global
Genes Grant to the amount of
$4,800 for costs in training Peer
Coaches. The training materials
will be completed and the training
will begin shortly with travel to the
in-person training session sched-
uled with the Peer Coaches.
Training has already begun for PC
Advocates who will represent PC
Project in public meetings. The six
USA PC Advocates will have a
training session May 9, and will
attend the IPCC on May 10-11.
2386 East Heritage Way, Ste B, Salt Lake City, UT 84109 · www.pachyonychia.org · Phone 877-628-7300 · Email: [email protected]
IPCC News Brief Jan-Feb-Mar 2016 Vol 13, No 1 Page 3
THE BURDEN OF RARE In preparation for the International
PC Consortium Annual Meeting,
we often ask leading researchers to
also invite young investigators
who may be interested in a rare,
genetic, skin disease. This thought-
ful response was a powerful re-
minder of the challenges of a rare
disease with no effective treat-
ment. The statement is true for
every country in the world includ-
ing the USA which is considered a
‘research’ country.
If a rare disease has a treatment,
physicians have something to offer
patients and are glad to see them
and prescribe for them. When a
rare disease has a completely un-
met medical need, the burden for
these patients is far greater.
Ultra Rare Disease Burden
—no effective treatment
Misdiagnosis
Misunderstanding
Misinformation
Isolation (feeling alone)
Pachyonychia Congenita
Pain
Appearance
Time for care
No treatment (unmet medical
need)
RARE DISEASE DAY
FEBRUARY 29, 2016 To lead up to Rare Disease Day,
NORD is holding a special count-
down on social media. PC Project
was lucky enough to be selected as
one of 28 NORD member organi-
zations to be highlighted. PC Pro-
ject will be spotlighted on
Wednesday, February 24, 2016 on
the NORD Facebook page. We
will also have a tweet posted in the
Twitter Chat for rare diseases
which will be on March 1st.
GENE THERAPY, EDITING
OR CORRECTION PC patients are often unclear about
the type of gene therapy drugs we
are pursing for PC to stop the mu-
tant gene from acting. We often
need to explain that when these
drugs are available for patient, the
drugs will have no effect on off-
spring.
The ethical debate on these topics,
especially when treatment affects
the next generations, is very much
in the news at present as scientific
advances continue. Recently, the
National Academies of Sciences
held a ‘Gene Editing Summit.’
At the summit, a short presentation
by Sharon Terry, CEO of Genetic
Alliance, included many points
raised by patient and advocates.
Her presentation is available at https://vimeo.com/album/3703972/
video/149190935
Videos of the entire summit are
available at http://nationalacademies.org/gene-
editing/Gene-Edit-Summit/webcast/
index.htm
JERRY SEINFELD DONATES
$160,000 TO PC PROJECT The website Look to the Stars has
a short article about Jerry donating
the proceeds from the Salt Lake
show to PC Project. Also a link to
our YouTube ‘Thank You’ video.
https://jerry-seinfeld-donates-show
-proceeds-to-charity
RECENT PUBLICATIONS Haber RM, Rose TH. Identifica-
tion of a CAST Mutation in a Co-
hort Previously Misdiagnosed as
Having Autosomal Recessive
Pachyonychia Congenita. JAMA
Dermatol. 2015 Dec 1;151:1393-
1394
Has C, Technau-Hafsi K
Palmoplantar keratodermas: clini-
cal and genetic aspects. J Dtsch
Dermatol Ges. 2016;14:123-40.
Kaspar RL, Hickerson RP, Gonzá-
lez-González E, Flores MA,
Speaker TP, Rogers FA, Milstone
LM, Contag CH. Imaging Func-
tional Nucleic Acid Delivery to
Skin. Methods Mol Biol.
2016;1372:1-24.
Liao C, Xie G, Zhu L, Chen X, Li
X, Xu B, Ramot Y, Paus R, Yue Z.
p53 is a Direct Transcriptional Re-
pressor of Keratin 17: Lessons
from a Rat Model of Radiation
Dermatitis. J Invest Dermatol.
2015 Dec 30.
Micol-Martínez O, López-
González V, Garcia-Marcos PW,
Martínez-Menchón T, Guillén-
Navarro E. Congenital pachy-
onychia: A new case associated
with the KRT17 gene. An Pediatr
(Barc). 2015 Dec 24.
“I don't know anybody around
who is especially interested in
this area. Because (Turkey) is
not a ‘Research Country’, physi-
cians usually don't want to en-
gage with diseases (and fami-
lies) whose treatment has not
yet been found. I haven't heard
of anyone even from my derma-
tologist friends.” Volkan Okur
MD Columbia University, NY
2386 East Heritage Way, Ste B, Salt Lake City, UT 84109 · www.pachyonychia.org · Phone 877-628-7300 · Email: [email protected]
Page 4 IPCC News Brief Jan-Feb-Mar 2016 Vol 13, No 1
SCHEDULE
Tuesday, May 10
7am breakfast
8:30am sessions begin
Lunch break
1:30pm session continue to 4pm
6:30pm dinner meeting offsite
Wednesday, May 11
7am breakfast
8:30am sessions begin
Meeting ends 12noon
Ofir Artzi
Andreas Berroth
Anna Bruckner
Christopher G. Bunick
Jiang Chen
Pierre A. Coulombe
Ruth Defrin
C. David Hansen
Alain A. Hovnanian
Roger L. Kaspar
Michelle Kerns
E. Birgitte Lane
Edel A. O'Toole
Volkan Okur
Michael Polydefkis
Amy S. Paller
Laure Rittié
Frances J.D. Smith
Eli Sprecher
Jakub Tolar
Karen Wagner
Yong Yang
INVITED SPEAKERS AND ATTENDEES
13th Annual
International Pachyonychia Congenita
Consortium (IPCC) Symposium
May 10-11, 2016 just prior to the SID Annual meeting
in Phoenix, Arizona at the
Westin Kierland Resort & Spa!
Please register at www.surveymonkey.com/r/2016IPCC The registration fee is waived with pre-registration; sessions & meals included.
IPCC NEWS BRIEF
Keeping
Connected
with
Keratins by Emily Warshauer, MD
University of Colorado
Keeping connected may be easier
said than done. In our fast-paced
and ever-changing environments,
we are vulnerable to stress and lost
connections with each other. Sim-
ilarly, as an extraordinarily dy-
namic entity, the skin is also prone
to great stress and easily suscepti-
ble to disassembly. Yet, the skin
is remarkably resilient and has the
capacity to withstand a great deal
due to its impressively tight bonds.
So how does it accomplish this
task? The keratins are fundamen-
tal to this effort and represent a
true tour de force.
In the January 2016 publication of
the Journal of Investigative Der-
matology, Loschke and colleagues
examined how the quality and
quantity of keratins contribute to
desmosome adhesion and preserve
the integrity of the skin. Investi-
gating isotype-specific keratin
functions, stable keratinocyte cell
lines re-expressing type I keratins
K14 or K17 or type II keratins K5
or K6 were established among a
keratin null background. Findings
revealed that K5/K14 filaments
stabilize desmosomes and se-
quester protein kinase C alpha
(PKCα) in the cytoplasm whereas
the “wound healing” keratins K6/
K17 induce desmosome disassem-
bly mediated by PKCα transloca-
tion to the plasma membrane to
initiate the crucial process of re-
epithelialization.
In the December 2015 publication
of the Journal of Cell Biology, Ku-
mar and colleagues sought to es-
tablish a mechanistic link between
the keratins, cornified envelope
composition and function by utiliz-
ing comparative proteomics of
cornified envelopes (CEs) generat-
ed from mice lacking all type I &
II keratins. Findings revealed the
dysregulation of many CE constit-
uents including DSG1, hornerin
and filaggrins, recognizing keratin
scaffolds as essential to the corni-
fied envelope. Additional immu-
nofluorescence studies also dis-
played keratin control of mito-
chondrial lipid composition and
activity, thus markedly expanding
our understanding of the breadth
and depth of the keratin network
within the epidermis.
New mechanisms elucidated here
highlight the synergy required of
various keratin isotopes to main-
tain the complex interconnections
within the epidermis. The mecha-
nistic and functional importance of
these keratin connections is vital
knowing that severe keratinopa-
thies and barrier defects result as
layers of connections start to un-
ravel. The deliberate keratin con-
nections and the concerted effort
to maintain them serve as a great
role model in the skin and beyond
to bridge gaps across boundaries.
Loschke F, Homberg M, Magin
TM. Keratin Isotypes Control Des-
mosome Stability and Dynamics
through PKCα.
J Invest Dermatol. 2016 Jan.
Kumar V, Bouameur JE, Bär J,
Rice RH, Hornig-Do HT, Roop
DR, Schwarz N, Brodesser S,
Thiering S, Leube RE, Wiesner
RJ, Vijayaraj P, Brazel CB, Heller
S, Binder H, Löffler-Wirth H,
Seibel P, Magin TM. A keratin
scaffold regulates epidermal barri-
er formation, mitochondrial lipid
composition, and activity.
J Cell Biol. 2015 Dec.
PC ADVOCATE TRAINING Training for the first eight PC Ad-
vocates was held May 9, 2016 in
Scottsdale, Arizona just prior to
the IPCC symposium.
The 8 PC Advocates are patients/
parents from across the USA, with
various PC types. They are the PC
experts and were joined by IPCC
physicians and scientists (the PC
specialists) for an inter-active
training session. Those IPCC
members attending included C.
David Hansen, Peter Hein, Roger
L. Kaspar, Michael J. Polydefkis,
2386 E Heritage Way, Suite B, PO Box 9010, Salt Lake City, UT 84109 · www.pachyonychia.org · 877-628-7300 · [email protected]
Vol 13, No. 2 Apr-May-Jun 2016
2386 E Heritage Way, Suite B, PO Box 9010, Salt Lake City, UT 84109 · www.pachyonychia.org · 877-628-7300 · [email protected]
Page 2 IPCC News Brief Apr-May-Jun 2016 Vol 13, No 2
Vu Van Quang, Laure Rittié, and
Frances J.D. Smith.
The PC Advocate training project
in the USA was made possible in
part through a generous grant
from Global Genes.
INTERNATIONAL
PACHYONYCHIA CONGENITA
CONSORTIUM (IPCC) by Frances Smith, PhD
PC Project
The13th Annual Research Sympo-
sium of the International Pachy-
onychia Congentia Consortium
(IPCC) was held on May 10-11,
2016 in Scottsdale, Arizona. The
meeting was attended by about 40
physicians and scientists from
around the world. The first ses-
sion, chaired by Laure Ritte, start-
ed with presentations about the
genetics of PC and other rare skin
disorders (Frances Smith and Eli
Sprecher), followed by Pierre Cou-
lombe who presented 'Keratin mu-
tation vs pathogenesis in PC: Chal-
lenges and opportunities'. He dis-
cussed that despite the very similar
sequence homology between
keratins K14, K16 and K17 they
have very different functions as
shown by the distinct null pheno-
types in mouse models.
This introductory talk on the com-
plex keratin ecosystem of plantar
epidermis was a great introduction
for a later presentation by Michelle
Kerns who spoke about the 'Role
of oxidative stress and dysfunc-
tional Nrf2 in PC-associated
palmoplantar keratoderma'. This
study has very recently been pub-
lished in J Clin Invest. She showed
that oxidative stress and dysfunc-
tional Nrf2 act as contributors to
PPK pathogenesis, K16 is a regu-
lator of Nrf2 activation and that
pharmacological activation of Nrf2
should be further explored for PC
treatment.
Catherine Pei-Ju reported on her
recent studies 'Stem cells in the
sweat glands: wound repair and
regeneration' and Andreas Berroth
gave an update on his work involv-
ing miRNAs, 'Insights into the role
of miRNAs in PC.
The findings of a pain study con-
ducted on 62 patients with con-
firmed PC at three patient support
meetings (in Paris, France; Edin-
burgh, Scotland and Newark,
USA) and 45 matched controls
were reported by Silviu Brill. The
research questions were (1) Are
PC patients experiencing neuro-
pathic pain? and (2) was there a
different prevalence between dif-
ferent genotypes? A systematic
quantitative controlled study was
performed using conduction tests,
pain modulation tests and pain &
QOL questionnaires. Results were
presented and the final conclusion
was that there were sufficient signs
to assume the presence of periph-
eral neuropathic pain.
Dennis Roop reported on the excit-
ing progress in his lab to develop
'Stem cell therapies for EB'. They
have developed a successful proto-
col for growing iPS cells and are
moving forward towards the clini-
cal application of iPS cell-based
therapy for patients with recessive
dystrophic epidermolysis bullosa
(RDEB) and a particular COL7A1
mutation.
The afternoon session, chaired by
Roger Kaspar, began with a
presentation by Jiang Chen 'Cell to
cell adhesion relative to blistering'.
Karen Wagner spoke about soluble
epoxide hydrolase inhibitors in her
presentation 'Analgesia mediated
by soluble epoxide hyrolase inhibi-
tion and epoxy fatty acid metabo-
lites'. She showed how they are
effective in clinical conditions in
animals and concluded that they
2386 E Heritage Way, Suite B, PO Box 9010, Salt Lake City, UT 84109 · www.pachyonychia.org · 877-628-7300 · [email protected]
IPCC News Brief Apr-May-Jun 2016 Vol 13, No 2 Page 3
are being developed as a potential
therapy for neuropathic pain and
how this might be relevant for PC.
Birgit Lane gave an overview on
the growth of skin research in Sin-
gapore and discussed on-going
studies in her lab on cell models of
EBS.
Maria Morasso reported on her
recent study identifying SNPs pre-
sent in different keratins expressed
in tooth enamel. Teeth were col-
lected from PC patients to deter-
mine if there is any relationship
between PC and dental caries.
Tycho Speaker spoke about a
FlexPad soluble microneedle array
as an alternative to ID injection to
administer botulinum toxin to
mouse footpads. He also described
and demonstrated a PVA/starch
membrane they had developed as
an alternative approach to the tra-
ditional starch/iodine test to detect
and quantify small quantities of
sweat.
Christopher Bunick gave an update
on his x-ray crystallography stud-
ies entitled 'Defining the chemical
and structural properties of human
keratins using x-ray crystallog-
raphy'.
At the end of the first day, a spe-
cial dinner event was hosted at the
home of Jack Padovano, a Pachy-
onychia Congenita patient and Ad-
vocate for PC Project. The food
was delicious and the lovely
poolside setting created a pleasant
informal setting for discussions
and planning collaborations.
The second day was chaired by Eli
Sprecher. Several presentations
and discussions focussed on pro-
posed clinical trials and the im-
portance of what, and how to
measure clinical endpoints to eval-
uate these studies.
Peter Hein from Grünethal Group,
gave us an insight into pain - how
the brain produces the pain, not the
body/organ. Pain is complex and
multidimensional as it is a sensory
experience/event, has a conscious/
cognitive component, an emotion-
al/affective component and a moti-
vating component dimension. He
went on to discuss setting clinical
endpoints for pain and different
ways to measure pain - 'classical '
pain scales (typically uni-
dimensional), pain measurement
by tools and questionnaires and
multidimensional scales. He con-
cluded that pain is what the patient
feels and there are many factors
that drive variability which may
obscure true treatment effects in-
cluding effectiveness of interven-
tion, site performance, treatment
history and random variability.
Michael Polydefkis presented his
recent findings 'Quantitative analy-
sis of cutaneous neuroanatomy in
PC patients' - a recent study com-
paring patterns of cutaneous inner-
vation from affected and unaffect-
ed plantar skin biopsies from pa-
tients with PC and control sub-
jects. The histological findings
suggest that alterations in PC ex-
tend beyond keratinocytes and
may provide strategies to study
neuropathic pain in PC.
Alain Hovnanian showed that the
mTOR pathway is activated in le-
sional skin from Olmsted syn-
drome patients with a TRPV3 mu-
tation and reported on the use of
topical sirolimus for the treatment
of one case.
Edel O'Toole talked about the
mechanism of action of oral retin-
oids, lab studies to support this and
the revised clinical trial plan for
retinoids.
IPCC Dinner, May 10, 2016—at the home of Jack Padovano, PC Advocate
2386 E Heritage Way, Suite B, PO Box 9010, Salt Lake City, UT 84109 · www.pachyonychia.org · 877-628-7300 · [email protected]
Page 4 IPCC News Brief Apr-May-Jun 2016 Vol 13, No 2
Details of another proposed clini-
cal trial, botulinum toxin injections
into plantar calluses, was presented
by Ofir Artzi. The trial plan was
discussed followed by a discussion
of the pros and cons of various
endpoints which might be used to
evaluate the trial. Ideas included a
standard pain scale, PC Quality of
Life questionnaire developed by
Peter Hull, an activity monitor, pa-
tient diary and clinical photo-
graphs.
The final talks focussed on aspects
of the nail. Campbell Stewart
shared the results of his study on
'The histological features of the
nail plate in PC' and Frances Smith
presented findings on a retrospec-
tive study 'Nail removal as a PC
treatment' followed by a discussion
led by Albert Bravo and David
Hansen.
The symposium ended with a re-
minder that the IPCRR data is 'A
treasure trove of information on
PC' and readily available to IPCC
members for studies and articles.
Following the main IPCC meeting
on May 11th, the IPCC Steering
Committee and guests met for a
brainstorming session focused on
clinical trial design.
EUROPEAN CONFERENCE ON
RARE DISEASES The 8th European Conference on
Rare Diseases & Orphan Products
was held in Edinburgh May 26-28,
2016. The aim of these conferences
is to unite all rare disease stake-
holders from all European nations -
patients and patient representa-
tives, healthcare professionals and
researchers, industry, payers, regu-
lators and policy makers in the
fight against rare diseases. The
overall theme was 'Game changers
in Rare Disease - Delivering 21st
century healthcare to rare disease
patients: Together we can change
the future'. Approximately 800 par-
ticipants and over 80 speakers met
to cover six themes of Game
Changers - in research, diagnosis,
drug development, authorisation &
access, care provision, social poli-
cy and in global society. As well as
individuals from Europe, there
were also representatives from in-
dustry and patient groups from
USA, China, India, South Africa,
New Zealand and Australia.
Emphasis was placed on the strong
need for everyone to co-operate
and collaborate not just within Eu-
rope but globally to benefit all rare
disease patients from diagnosis to
care and treatment. Many examples
were given to show how with new
technologies it is easier to connect
and build communities. There were
presentations and discussions about
the European Reference Networks
(ERN) being set up to work across
borders, across different jurisdic-
tions etc to connect experts and
highly specialised services to serve
all rare disease patients. Feeding
into these discussions were two
video presentations by members of
NIH National Center for Advanc-
ing Translational Sciences (NCATS)
in the USA. The opportunity to
learn from each other so less ad-
vanced regions in a given field can
benefit from experience sharing
with other areas in Europe and
globally will lead to more effective
outcomes.
RECENT PUBLICATIONS Deng Y, Chen J, Zhao Y, Yan X, Zhang
L, Choy K, Hu J, Sant HJ, Gale BK,
Tang T. Transdermal Delivery of siRNA
through Microneedle Array.Sci Rep.
2016 Feb 18;6:21422.
Edwards KA, Terry SF, Gold D, Horn
EJ, Schwartz M, Stuart M, Vernon SD.
Realizing Our Potential in Biobanking: Disease Advocacy Organizations Enliv-
en Translational Research. Biopreserv
Biobank. 2016 Apr 8.
Forrest CE, Casey G, Mordaunt DA,
Thompson EM, Gordon L. Pachyonych-
ia Congenita: A Spectrum of KRT6a
Mutations in Australian Patients. Pedi-
atr Dermatol. 2016 May;33(3):337-42.
Has C, Technau-Hafsi K. Palmoplantar
keratodermas: clinical and genetic as-
pects. J Dtsch Dermatol Ges. 2016
Feb;14(2):123-39.
Kerns ML, Hakim JM, Lu RG, Guo Y,
Berroth A, Kaspar RL, Coulombe PA.
Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita
phenotypes. J Clin Invest. 2016 Jun
1;126(6):2356-66.
Ni C, Yan M, Zhang J, Cheng R, Liang
J, Deng D, Wang Z, Li M, Yao Z. A
novel mutation in TRPV3 gene causes
atypical familial Olmsted syndrome. Sci
Rep. 2016 Feb 23;6:21815.
Rathore PK, Khullar V, Das A. Pachy-onychia Congenita Type 1: Case Report
and Review of the Literature. Indian J
Dermatol. 2016 Mar-Apr;61(2):196-9.
Sakiyama T, Kubo A. Hereditary
palmoplantar keratoderma "clinical and
genetic differential diagnosis". J Derma-
tol. 2016 Mar;43(3):264-74.
Tariq S, Schmitz ML, Kanjia MK.
Chronic Foot Pain due to Pachyonychia
Congenita in a Pediatric Patient: A Suc-
cessful Management Strategy. A Case
Rep. 2016 May 15;6(10):305-7.
IPCC NEWS BRIEF
KEEPING AN EYE
ON THE KERATINS
Emily Warshauer MD
Univ of Colorado
Eyesight is fundamental as one of
our five senses to see our sur-
roundings. Vision involves our
eyes working in coordination with
our brain to interpret and interact
with the world around us. Critical
thinking, scientific discovery and
progress all require vision.
With our eyes on the keratins, a
similar vision is required to more
completely understand the struc-
ture and function of these proteins.
Keratin 3 (KRT3) and Keratin 12
(KRT12) come to the forefront,
both playing a special role in the
eye as cornea-specific keratins and
implicated in corneal dystrophies.
In the March 2016 issue of Human
Molecular Genetics, Allen and
colleagues sought to further inves-
tigate the pathomechanism of
Meesmann epithelial corneal dys-
trophy (MECD) and shed light on
the eye-specific keratins. They
generated and phenotypically char-
acterized a knock-in humanized
mouse model carrying the severe
MECD-associated K12-Leu132Pro
mutation. While no alterations in
corneal opacity were detected by
slit-lamp examination, disor-
ganized corneal epithelium with
cell fragility and rupture of epithe-
lial cysts at the corneal surface
were revealed. Interestingly, the
K12-Leu132Pro mutation caused
an altered keratin profile with up-
regulation of KRT6, KRT16 and
KRT14 consistent with the stress
response to compensate for de-
creased integrity of the cytoskele-
ton. In contrast to the human
MECD cornea, KRT5 expression
is decreased in the mouse genome,
hypothesized to be due to a lack of
a KRT3 equivalent.
Within the classical group of dom-
inant-negative genetic disorders,
Meesmann epithelial corneal dys-
trophy has been a focus for the de-
velopment of allele-specific thera-
peutic siRNA. In the 2011 publi-
cation of PloS One, Liao and col-
leagues adapted the siRNA se-
quence walk methodology to de-
sign a potent siRNA against the
mutant allele K12-Leu132Pro.
Furthermore, in the 2014 publica-
tion of Investigative Ophthalmolo-
gy & Visual Science, Courtney and
colleagues confirmed the siRNA
approach as a viable treatment op-
tion within the context of an effec-
tive delivery vehicle.
True vision is key to fully realize
the potential of RNA interference
therapeutics for the prevention of
Meesmann epithelial corneal dys-
trophy in addition to other
keratinopathies including Epider-
molysis Bullosa Simplex and
Pachyonychia Congenita.
References:
Allen EH, Courtney DG, Atkinson
SD, Moore JE, Mairs L, Poulsen
ET, Schiroli D, Maurizi E, Cole C,
Hickerson RP, James J, Mur-
gatroyd H, Smith FJ, MacEwen C,
Enghild JJ, Nesbit MA, Leslie
Pedrioli DM, McLean WH, Moore
CB. Keratin 12 missense mutation
induces the unfolded protein re-
sponse and apoptosis in Meesmann
epithelial corneal dystrophy. Hum
Mol Genet. 2016 Mar 15.
Courtney DG, Atkinson SD, Allen
EH, Moore JE, Walsh CP, Pedrioli
DM, MacEwen CJ, Pellegrini G,
Maurizi E, Serafini C, Fantacci M,
Liao H, Irvine AD, McLean WH,
Moore CB. siRNA silencing of
the mutant keratin 12 allele in cor-
neal limbal epithelial cells grown
from patients with Meesmann's
epithelial corneal dystrophy. In-
vest Ophthalmol Vis Sci. 2014
May 6.
Liao H, Irvine AD, Macewen CJ,
Weed KH, Porter L, Corden LD,
Gibson AB, Moore JE, Smith FJ,
McLean WH, Moore CB.
Development of allele-specific
therapeutic siRNA in Meesmann
epithelial corneal dystrophy. PloS
One. 2011.
2386 East Heritage Way, Ste B, Salt Lake City, UT 84109 · www.pachyonychia.org · Phone 877-628-7300 · Email: [email protected]
Vol 13, No. 3 Jul-Aug-Sep 2016
2386 East Heritage Way, Ste B, Salt Lake City, UT 84109 · www.pachyonychia.org · Phone 877-628-7300 · Email: [email protected]
Page 2 IPCC News Brief Jul-Aug-Sep 2016 Vol 13, No 3
We are pleased and excited to offi-
cially announce that topical siroli-
mus (TD201) for PC patients will
be advancing towards its next hu-
man clinical study. TransDerm has
recently partnered with Palvella
Therapeutics, a Philadelphia-based
company focused on relentlessly
and selflessly serving individuals
suffering from rare diseases
(Palvella, in Finnish, means “to
serve”), to rapidly advance the
program. Palvella’s core compe-
tencies involve developing and
commercializing novel rare dis-
ease therapies in the US, Europe,
and other geographies. Many of
you will have the opportunity to
hear more about Palvella and meet
their leadership team in the months
to come.
Consistent with the goals of any
initial study of an experimental
therapy in a rare disease, the Phase
Ib study of topical sirolimus eluci-
dated several key learning points
about the potential for this therapy
in PC. The study met its primary
objective of demonstrating the
safety of topical administration of
sirolimus cream for the treatment
of painful plantar keratoderma in
PC. Topical sirolimus demonstrat-
ed an excellent safety profile: there
were few local and systemic ad-
verse events, no serious adverse
events, and overall the topical siro-
limus cream was well tolerated.
The path forward for topical siroli-
mus in PC will now involve the
Palvella and TransDerm teams
working closely together to build
upon the novel formulation devel-
oped at TransDerm and explore
the potential to optimize that for-
mulation for the benefit of PC pa-
tients. Once that analysis is com-
plete and the FDA has been
properly engaged on the status and
plans of the program, topical siro-
limus will be poised to enter its
next clinical study, which will
more thoroughly evaluate thera-
peutic efficacy.
Thanks to all of you for your en-
gagement over many years to ad-
vance this promising therapy for
PC patients. Success going for-
ward will again necessitate the
same extraordinary level of collab-
oration, and we will again aim to
harness the collective wisdom and
expertise to design and enroll the
next clinical study.
WORKSHOP ON RARE SKIN
DISEASES, OCTOBER 20-21
IN MADRID, SPAIN The Foundation Ramon Areces has
organized a workshop on Rare
Skin Diseases in Madrid on
October 20-21 covering five main
topics: -Keratinization Disorders
-Diseases of Dermo-Epidermal
Fragility
-DNA Repair Diseases
-Ectodermal Dysplasias
-Vascular Diseases (genetic origin
cancer and clinical aspects)
Registration is free. For additional
information contact Fernando
Larcher, PhD at
PC PROJECT TO HOST
MEETINGS IN MADRID AND
EDINBURGH IN OCT 2016 Following the Rare Disease con-
ference, PC Project will host a
meeting for patients and research-
ers in Madrid, Spain. Beginning
with a dinner on Friday, October
21 at the NH Nactional Hotel, pa-
tients and researchers will enjoy
presentations and discussion on
Saturday, October 22 from 9am to
4pm. If interested, please email
The 2016 PC Patient Support
Meeting will be held in Edinburgh
for patients and researchers. The
event begins with a dinner on Fri-
day, October 28 with presentations
from major leaders in PC research
throughout the day on Saturday
and one-half day on Sunday. Reg-
istration is required. If you are in-
terested in attending, please email
TOPICAL SIROLIMUS UPDATE
Roger Kaspar,
TransDerm
Wesley Kaupinen
Palvella Therapeutics
2386 East Heritage Way, Ste B, Salt Lake City, UT 84109 · www.pachyonychia.org · Phone 877-628-7300 · Email: [email protected]
IPCC News Brief Jul-Aug-Sep 2016 Vol 13, No 3 Page 3
RECENT PUBLICATIONS Bornert O, Peking P, Bremer J,
Koller U, van den Akker PC,
Aartsma-Rus A, Pasmooij AM,
Murauer EM, Nyström A. RNA-
based therapies for genodermato-
ses. Exp Dermatol. 2016 Jul 4 Cammarata-Scalisi F, Natsuga K,
Toyonaga E, Nishie W, Shimizu
H, Avendaño A, Araque D, Da
Silva G, Bellacchio E, Callea M.
Early severe pachyonychia con-
genita subtype PC-K6a with a nov-
el mutation in the KRT6A gene. J
Eur Acad Dermatol Venereol.
2016 Jul 21
Hobbs RP, Jacob JT, Coulombe
PA. Keratins Are Going Nuclear.
Dev Cell. 2016 Aug 8;38(3):227-
33
Holahan HM, Farah RS, Ferguson
NN, Paller AS, Legler
AA.Treatment of symptomatic epi-
dermolysis bullosa simplex with
botulinum toxin in a pediatric pa-
tient. JAAD Case Rep. 2016 Jul
14;2(3):259-60.
Lovgren ML, McAleer MA, Irvine
AD, Wilson NJ, Tavadia S,
Schwartz ME, Cole C, Sandilands
A, Smith FJ, Zamiri M. Mutations
in desmoglein-1 cause diverse in-
herited palmoplantar keratoderma
phenotypes: Implications for ge-
netic screening.
Br J Dermatol. 2016 Aug 18
Kumar V, Behr M, Kiritsi D,
Scheffschick A, Grahnert A, Hom-
berg M, Schwieger-Briel A, Jakob
T, Bruckner-Tuderman L, Magin
TM. Keratin-dependent thymic
stromal lymphopoietin expression
2386 East Heritage Way, Ste B, Salt Lake City, UT 84109 · www.pachyonychia.org · Phone 877-628-7300 · Email: [email protected]
Page 4 IPCC News Brief Jul-Aug-Sep 2016 Vol 13, No 3
suggests a link between skin blis-
tering and atopic disease.
J Allergy Clin Immunol. 2016 Jun
15
Rittié L, Farr EA, Orringer JS,
Voorhees JJ, Fisher GJ. Reduced
cell cohesiveness of outgrowths
from eccrine sweat glands delays
wound closure in elderly skin. Ag-
ing Cell. 2016 May 17
Schiller SA, Seebode C, Wieser
GL, Goebbels S, Ruhwedel T, Hor-
owitz M, Rapaport D, Sarig
O,Sprecher E, Emmert S. Non-
keratinocyte SNAP29 influences
epidermal differentiation and hair
follicle formation in mice. Exp
Dermatol. 2016 Aug;25(8):647-9
Cindy Byers Atha
Executive Director
Pachyonychia Congenita Project
PC PROJECT APPOINTS NEW
EXECUTIVE DIRECTOR Staff members at PC Project (Mary
Schwartz, Frances Smith and Holly
Evans) are thrilled to introduce the
new Executive Director for PC
Project to our IPCC members.
Mary says “I am certain the goal
we have all shared over the last
years — to develop and deliver
effective treatments for PC patients
— will move forward and be
achieved under Cindy’s
leadership.”
Cindy Byers Atha is a Healthcare
Executive with a 26-year history of
Commercial experience in a series
of increasingly responsible Sales
and Marketing roles at Atossa Ge-
netics, Depomed, Inc., and Amylin
Pharmaceuticals, innovative bio-
tech/biopharmaceutical companies,
as well as AstraZeneca, one of the
world’s leading pharmaceutical
companies. She most recently was
the Vice President of Sales and
Marketing at Atossa Genetics
where she led commercialization
efforts for pharmacogenomic test-
ing and medical devices for Breast
Health. Previously, she was Vice
President of Managed Markets and
Trade with Depomed overseeing
Managed Care Sales and Market-
ing, Pricing, Contracting, Trade,
and Distribution. While at
Depomed, her team was recog-
nized by Healthcare Distribution
Management Association (HDMA)
as 2014 DIANA Winner for Best
Manufacturer and while perform-
ing a similar role at Amylin, her
team was twice recognized for
“Best Marketing Programs and
People” for a small manufacturer
and achieved the 2012 DIANA
Award for best new product intro-
duction. Ms. Atha began her phar-
maceutical career in field sales
with Merck & Co. and then moved
to AstraZeneca where she ad-
vanced into Senior Sales Leader-
ship. She was the recipient of more
than 16 sales awards for exception-
al individual and group perfor-
mance and AstraZeneca’s highly
prestigious “Leadership Excellence
Award” and "Global Challenge
Award." She helped bring over 16
new pharmaceutical products to
market. Early in her career, she
was recognized by several key
healthcare clients as the best ac-
count representative in the indus-
try. She gained formative experi-
ence as an Account Executive with
Scientific Technologies, promoting
the sale of research and medical
equipment to leading biotechnolo-
gy companies and medical centers.
Ms. Atha also serves on the Board
of Directors for Operation of Hope,
a non-profit organization that pro-
vides facial reconstructive surger-
ies to poor children around the
world. She is a member of the
Academy of Managed Care Phar-
macy and a volunteer mentor for
BoomStartup. She received her
Bachelor of Science in Zoology
from North Carolina State Univer-
sity in Raleigh, North Carolina.
She and her husband William re-
side in Salt Lake City, UT.
PC ADVOCATES TRAINING Beginning with eight patients in
the USA, PC Project has begun a
program to educate, inspire and
involve patients as advocates in
their own communities.
Ten patients from England, Fin-
land, France, Germany, India,
Spain, The Netherlands and Wales
are completing webmeeting train-
ing sessions and will meet in Edin-
burgh just prior to the Patient Sup-
port Meeting for an in-person train-
ing session with IPCC leaders.