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: info@pachyonychia.org

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: info@pachyonychia.org

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.

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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

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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,

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Vol 13, No. 2 Apr-May-Jun 2016

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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

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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 · info@pachyonychia.org

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: info@pachyonychia.org

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: info@pachyonychia.org

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

fernando.larcher@ciemat.es

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

info@pachyonychia.org

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

info@pachyonychia.org.

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: info@pachyonychia.org

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: info@pachyonychia.org

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.