IPCC NEWS BRIEF Vol 13, No. 1 Jan-Feb-Mar 2016

MAY THE cytoskeleton through a loss 2001 in the Journal of Investiga- FORCE of plectin facilitated greater nucle- tive Dermatology, Sprecher and BE WITH ar deformation via reduced keratin colleagues performed structural filament density around the nucle- analyses and identified that a se- us. vere form of epidermal hyperkera- by Emily Warshauer MD tosis ( hystrix Curth- University of Colorado Plectin constitutes such an im- Macklin) resulted from a unique portant mediator of forces in the in the variable tail do- According to the Jedi master Obi- maintenance of the substantial ker- main of Keratin 1 (KRT1). This Wan Kenobi in the Star Wars uni- atin network that a loss of plectin defect was associated with a lack verse, “The Force is what gives a disrupts the keratin cytoskeleton so of keratin bundling and retraction Jedi his power. It’s an energy field detrimentally, resulting in severe of the cytoskeleton from the nucle- created by all living things…” forms of us, directly impacting nuclear Unifying forces provide a founda- Simplex (EBS): EBS with muscu- shape. Might plectin have also tion that enables any system to lar dystrophy, EBS with pyloric played a role? function effectively. The keratin atresia and EBS-Ogna. In the epi- network too derives strength and dermis of plectin-deficient epider- In conclusion, the linker stability from an impressive set of molysis bullosa simplex patients, plectin is clearly an important fig- powerful forces that have still yet keratinocytes were shown to have ure in the complex forces at play to be completely understood. abnormal nuclear morphologies. to maintain keratin stability. Just as Obi-Wan Kenobi was noble and In the recent December 2015 pub- Delving further into the versatility gifted, so too is plectin in the ways lication of the Journal of Cell Sci- of plectin, in the October 2015 of “the force” that it exerts to ence, Almeda and colleagues publication of the Journal of Cell maintain the keratin network. acknowledged the complexity of Science, Nahidiazar and colleagues forces involved in the control of utilized super-resolution microsco- References the keratin network organization. py to investigate additional keratin They recognized that the large cy- connections with plectin. Notably, Almeida F, Walko G, McMillan J, toskeletal linker protein, plectin, is they identified that plectin, in its McGrath J, Wiche G, Barber A, an essential regulator of nuclear role as a hemidesmosomal plaque Connelly J. The cytolinker plectin morphology and protects the nu- protein, interacts in a simultaneous regulates nuclear cleus from mechanical defor- and asymmetric fashion with beta- mechanotransduction in mation. The role of biophysical 4 integrin and keratin filaments. keratinocytes. J Cell Sci 2015. forces underlying the crosstalk be- This novel finding highlights intri- Dec 15. tween plectin and the nucleus has cate forces at work between kera- clearly been established, however tin filaments and plectin in the as- Nahidiazar L, Kreft M, van den the precise mechanism remains a sembly of hemidesmosomes. Broek B, Secades P, Manders EM, mystery. Utilizing micro- Sonnenberg A, Jalink K. The patterned substrates to Deciphering the elaborate details molecular architecture of manipulate cell shape, the authors of the keratin network has long hemidesmosomes, as revealed with identified that disruption of the been an ongoing effort. In April

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super-resolution microscopy. J year (as reported in a previous PC patients. A correct diagnosis is Cell Sci. 2015 Oct 15. IPCC NewsBrief) a mutation was important for patient care and ge- identified in this family in the netic counselling. Genetic testing Natsuga K. Plectin-related skin CAST gene that causes PLACK is available at no charge to patients diseases. J Dermatol Sci. 2015 syndrome (Lin et al., Loss-of- and physicians through the IPCRR Mar. function in CAST cause to provide a correct diagnosis and peeling skin, , acral avoid further misinformation in the Sprecher E. Evidence for Novel punctate keratoses, cheilitis, and literature. Functions of the Keratin Tail knuckle pads. Am J Hum Genet. Emerging From a Mutation 2015;96:440-7). For patients registered with the Causing . J IPCRR: Invest Dermatol. 2001 April. To avoid further misquoting of (1) genetic testing for the PC kera- recessive PC, Haber and Rose tin genes is FREE THE VALUE AND NECESSITY have recently published a paper, to (2) Testing is done using a saliva correct their previous diagnosis kit provided by PC Project (no OF GENETIC TESTING made in 1986 (before PC genes blood draw) and easy to ship sam- Frances Smith, Chief Scientific Officer, PC Project were know), 'Identification of a ple in the regular mail CAST mutation in a cohort previ- (3) best benefits for physician, pa- The International Pachyonychia ously misdiagnosed as having au- tient and family is to participate in Congentia Project Research Regis- tosomal recessive pachyonychia the registry try (IPCRR) established in 2004, congenita'. (Haber RM, Rose TH. has collected clinical and molecu- JAMA Dermatol. 2015;151:1393- PC Project is careful to work with lar data from nearly 700 PC pa- 1394). They stress the importance referring physicians on publica- tients. All are caused by a hetero- of genetic analysis to confirm a tions resulting from the testing and zygous mutation in KRT6A, clinical diagnosis, adding that provide many support services to KRT6B, KRT6C, KRT16 or along with Clouston syndrome, the patient and family. Please refer KRT17, and occur either as sponta- and others, PLACK syndrome is your patients and let your col- neous cases or with known autoso- another that may leagues know of this free service. mal dominant inheritance. Addi- mimic PC. tionally, in the literature, all other PC PROJECT AWARDED cases of PC with genetic testing To date, all genetically confirmed GLOBAL GENES GRANT are also autosomal dominant. cases of PC show autosomal domi- We are pleased to announce that nant inheritance. There are no PC Project was awarded a Global However, a couple of early papers known cases of autosomal reces- Genes Grant to the amount of report recessive PC, based on clin- sive PC confirmed by genetic anal- $4,800 for costs in training Peer ical diagnosis with no genetic test- ysis. Coaches. The training materials ing. One paper quoted many times will be completed and the training over the years is 'Autosomal reces- Clinical case reports are still pub- will begin shortly with travel to the sive pachyonychia congeni- lished as PC without genetic test- in-person training session sched- ta' (Haber RM, Rose TH. Arch ing, many of which, from the clini- uled with the Peer Coaches. Dermatol. 1986;122:919-23). Pub- cal description do not appear typi- lished in 1986, this clinical diagno- cal of PC. For example, character- Training has already begun for PC sis was prior to the identification istics such as baldness, deafness or Advocates who will represent PC of PC keratin gene mutations. We other features which are not asso- Project in public meetings. The six now know this is not recessive PC ciated with PC are identified in USA PC Advocates will have a but another rare skin disorder. Last these so-called ‘novel’ cases of PC training session May 9, and will with no genetic basis. This can be attend the IPCC on May 10-11. confusing for both physicians and

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THE BURDEN OF RARE RARE DISEASE DAY JERRY SEINFELD DONATES In preparation for the International FEBRUARY 29, 2016 $160,000 TO PC PROJECT PC Consortium Annual Meeting, To lead up to Rare Disease Day, The website Look to the Stars has we often ask leading researchers to NORD is holding a special count- a short article about Jerry donating also invite young investigators down on social media. PC Project the proceeds from the Salt Lake who may be interested in a rare, was lucky enough to be selected as show to PC Project. Also a link to genetic, skin disease. This thought- one of 28 NORD member organi- our YouTube ‘Thank You’ video. ful response was a powerful re- zations to be highlighted. PC Pro- https://jerry-seinfeld-donates-show minder of the challenges of a rare ject will be spotlighted on -proceeds-to-charity disease with no effective treat- Wednesday, February 24, 2016 on ment. The statement is true for the NORD Facebook page. We RECENT PUBLICATIONS every country in the world includ- will also have a tweet posted in the Haber RM, Rose TH. Identifica- ing the USA which is considered a Twitter Chat for rare diseases tion of a CAST Mutation in a Co- ‘research’ country. which will be on March 1st. hort Previously Misdiagnosed as Having Autosomal Recessive “I don't know anybody around GENE THERAPY, EDITING Pachyonychia Congenita. JAMA who is especially interested in OR CORRECTION Dermatol. 2015 Dec 1;151:1393- this area. Because (Turkey) is PC patients are often unclear about 1394 not a ‘Research Country’, physi- the type of gene therapy drugs we cians usually don't want to en- are pursing for PC to stop the mu- Has C, Technau-Hafsi K gage with diseases (and fami- tant gene from acting. We often Palmoplantar : clini- lies) whose treatment has not need to explain that when these cal and genetic aspects. J Dtsch yet been found. I haven't heard drugs are available for patient, the Dermatol Ges. 2016;14:123-40. of anyone even from my derma- drugs will have no effect on off- tologist friends.” Volkan Okur spring. Kaspar RL, Hickerson RP, Gonzá- MD Columbia University, NY lez-González E, Flores MA, Speaker TP, Rogers FA, Milstone The ethical debate on these topics, LM, Contag CH. Imaging Func- If a rare disease has a treatment, especially when treatment affects tional Nucleic Acid Delivery to physicians have something to offer the next generations, is very much Skin. Methods Mol Biol. patients and are glad to see them in the news at present as scientific 2016;1372:1-24. and prescribe for them. When a advances continue. Recently, the

rare disease has a completely un- National Academies of Sciences Liao C, Xie G, Zhu L, Chen X, Li met medical need, the burden for held a ‘Gene Editing Summit.’ X, Xu B, Ramot Y, Paus R, Yue Z. these patients is far greater. p53 is a Direct Transcriptional Re- At the summit, a short presentation pressor of : Lessons Ultra Rare Disease Burden by Sharon Terry, CEO of Genetic from a Rat Model of Radiation —no effective treatment Alliance, included many points Dermatitis. J Invest Dermatol.  Misdiagnosis raised by patient and advocates. 2015 Dec 30.  Misunderstanding Her presentation is available at https://vimeo.com/album/3703972/  Misinformation video/149190935 Micol-Martínez O, López-  Isolation (feeling alone) González V, Garcia-Marcos PW, Pachyonychia Congenita Martínez-Menchón T, Guillén-  Pain Videos of the entire summit are Navarro E. Congenital pachy-  Appearance available at http://nationalacademies.org/gene- onychia: A new case associated  Time for care editing/Gene-Edit-Summit/webcast/ with the KRT17 gene. An Pediatr  No treatment (unmet medical index.htm (Barc). 2015 Dec 24. need)

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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.

SCHEDULE INVITED SPEAKERS AND ATTENDEES Tuesday, May 10 7am breakfast Ofir Artzi E. Birgitte Lane Andreas Berroth Edel A. O'Toole 8:30am sessions begin Anna Bruckner Volkan Okur Lunch break Christopher G. Bunick Michael Polydefkis 1:30pm session continue to 4pm Jiang Chen Amy S. Paller 6:30pm dinner meeting offsite Pierre A. Coulombe Laure Rittié Ruth Defrin Frances J.D. Smith Wednesday, May 11 C. David Hansen Eli Sprecher 7am breakfast Alain A. Hovnanian Jakub Tolar 8:30am sessions begin Roger L. Kaspar Karen Wagner Michelle Kerns Yong Yang Meeting ends 12noon

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Keeping (PKCα) in the cytoplasm whereas ravel. The deliberate keratin con- Connected the “wound healing” keratins K6/ nections and the concerted effort with K17 induce desmosome disassem- to maintain them serve as a great bly mediated by PKCα transloca- role model in the skin and beyond Keratins tion to the plasma membrane to to bridge gaps across boundaries. by Emily Warshauer, MD initiate the crucial process of re- University of Colorado epithelialization. Loschke F, Homberg M, Magin TM. Keratin Isotypes Control Des- Keeping connected may be easier In the December 2015 publication mosome Stability and Dynamics said than done. In our fast-paced of the Journal of Cell Biology, Ku- through PKCα. and ever-changing environments, mar and colleagues sought to es- J Invest Dermatol. 2016 Jan. we are vulnerable to stress and lost tablish a mechanistic link between connections with each other. Sim- the keratins, cornified envelope Kumar V, Bouameur JE, Bär J, ilarly, as an extraordinarily dy- composition and function by utiliz- Rice RH, Hornig-Do HT, Roop namic entity, the skin is also prone ing comparative proteomics of DR, Schwarz N, Brodesser S, to great stress and easily suscepti- cornified envelopes (CEs) generat- Thiering S, Leube RE, Wiesner ble to disassembly. Yet, the skin ed from mice lacking all type I & RJ, Vijayaraj P, Brazel CB, Heller is remarkably resilient and has the II keratins. Findings revealed the S, Binder H, Löffler-Wirth H, capacity to withstand a great deal dysregulation of many CE constit- Seibel P, Magin TM. A keratin due to its impressively tight bonds. uents including DSG1, hornerin scaffold regulates epidermal barri- So how does it accomplish this and filaggrins, recognizing keratin er formation, mitochondrial lipid task? The keratins are fundamen- scaffolds as essential to the corni- composition, and activity. tal to this effort and represent a fied envelope. Additional immu- J Cell Biol. 2015 Dec. true tour de force. nofluorescence studies also dis-

played keratin control of mito- PC ADVOCATE TRAINING In the January 2016 publication of chondrial lipid composition and Training for the first eight PC Ad- the Journal of Investigative Der- activity, thus markedly expanding vocates was held May 9, 2016 in matology, Loschke and colleagues our understanding of the breadth Scottsdale, Arizona just prior to examined how the quality and and depth of the keratin network the IPCC symposium. quantity of keratins contribute to within the epidermis. desmosome adhesion and preserve The 8 PC Advocates are patients/ the integrity of the skin. Investi- New mechanisms elucidated here parents from across the USA, with gating isotype-specific keratin highlight the synergy required of various PC types. They are the PC functions, stable keratinocyte cell various keratin isotopes to main- experts and were joined by IPCC lines re-expressing type I keratins tain the complex interconnections physicians and scientists (the PC K14 or K17 or type II keratins K5 within the epidermis. The mecha- specialists) for an inter-active or K6 were established among a nistic and functional importance of training session. Those IPCC keratin null background. Findings these keratin connections is vital members attending included C. revealed that K5/K14 filaments knowing that severe keratinopa- David Hansen, Peter Hein, Roger stabilize desmosomes and se- thies and barrier defects result as L. Kaspar, Michael J. Polydefkis, quester protein kinase C alpha layers of connections start to un-

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Vu Van Quang, Laure Rittié, and cussed that despite the very similar ing miRNAs, 'Insights into the role Frances J.D. Smith. sequence homology between of miRNAs in PC. keratins K14, K16 and K17 they The findings of a pain study con- The PC Advocate training project have very different functions as ducted on 62 patients with con- in the USA was made possible in shown by the distinct null pheno- firmed PC at three patient support part through a generous grant types in mouse models. meetings (in Paris, France; Edin- from Global Genes. burgh, Scotland and Newark, This introductory talk on the com- USA) and 45 matched controls INTERNATIONAL plex keratin ecosystem of plantar were reported by Silviu Brill. The research questions were (1) Are PACHYONYCHIA CONGENITA epidermis was a great introduction for a later presentation by Michelle PC patients experiencing neuro- CONSORTIUM (IPCC) Kerns who spoke about the 'Role pathic pain? and (2) was there a by Frances Smith, PhD of oxidative stress and dysfunc- different prevalence between dif- PC Project tional Nrf2 in PC-associated ferent genotypes? A systematic palmoplantar '. This quantitative controlled study was The13th Annual Research Sympo- study has very recently been pub- performed using conduction tests, sium of the International Pachy- lished in J Clin Invest. She showed pain modulation tests and pain & onychia Congentia Consortium that oxidative stress and dysfunc- QOL questionnaires. Results were (IPCC) was held on May 10-11, tional Nrf2 act as contributors to presented and the final conclusion 2016 in Scottsdale, Arizona. The PPK pathogenesis, K16 is a regu- was that there were sufficient signs meeting was attended by about 40 lator of Nrf2 activation and that to assume the presence of periph- physicians and scientists from pharmacological activation of Nrf2 eral neuropathic pain. around the world. The first ses- should be further explored for PC sion, chaired by Laure Ritte, start- treatment. Dennis Roop reported on the excit- ed with presentations about the ing progress in his lab to develop genetics of PC and other rare skin Catherine Pei-Ju reported on her 'Stem cell therapies for EB'. They disorders (Frances Smith and Eli recent studies 'Stem cells in the have developed a successful proto- Sprecher), followed by Pierre Cou- sweat glands: wound repair and col for growing iPS cells and are lombe who presented 'Keratin mu- regeneration' and Andreas Berroth moving forward towards the clini- tation vs pathogenesis in PC: Chal- gave an update on his work involv- cal application of iPS cell-based lenges and opportunities'. He dis- 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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are being developed as a potential The second day was chaired by Eli tion, site performance, treatment therapy for neuropathic pain and Sprecher. Several presentations history and random variability. how this might be relevant for PC. and discussions focussed on pro- posed clinical trials and the im- Michael Polydefkis presented his Birgit Lane gave an overview on portance of what, and how to recent findings 'Quantitative analy- the growth of skin research in Sin- measure clinical endpoints to eval- sis of cutaneous neuroanatomy in gapore and discussed on-going uate these studies. PC patients' - a recent study com- studies in her lab on cell models of paring patterns of cutaneous inner- EBS. Peter Hein from Grünethal Group, vation from affected and unaffect- gave us an insight into pain - how ed plantar skin biopsies from pa- Maria Morasso reported on her the brain produces the pain, not the tients with PC and control sub- recent study identifying SNPs pre- body/organ. Pain is complex and jects. The histological findings sent in different keratins expressed multidimensional as it is a sensory suggest that alterations in PC ex- in tooth enamel. Teeth were col- experience/event, has a conscious/ tend beyond keratinocytes and lected from PC patients to deter- cognitive component, an emotion- may provide strategies to study mine if there is any relationship al/affective component and a moti- neuropathic pain in PC. between PC and dental caries. vating component dimension. He went on to discuss setting clinical Alain Hovnanian showed that the Tycho Speaker spoke about a endpoints for pain and different mTOR pathway is activated in le- FlexPad soluble microneedle array ways to measure pain - 'classical ' sional skin from Olmsted syn- as an alternative to ID injection to pain scales (typically uni- drome patients with a TRPV3 mu- administer botulinum toxin to dimensional), pain measurement tation and reported on the use of mouse footpads. He also described by tools and questionnaires and topical sirolimus for the treatment and demonstrated a PVA/starch multidimensional scales. He con- of one case. membrane they had developed as cluded that pain is what the patient an alternative approach to the tra- feels and there are many factors Edel O'Toole talked about the ditional starch/iodine test to detect that drive variability which may mechanism of action of oral retin- and quantify small quantities of obscure true treatment effects in- oids, lab studies to support this and sweat. cluding effectiveness of interven- the revised clinical trial plan for retinoids. 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.

IPCC Dinner, May 10, 2016—at the home of Jack Padovano, PC Advocate

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Details of another proposed clini- researchers, industry, payers, regu- RECENT PUBLICATIONS cal trial, botulinum toxin injections lators and policy makers in the Deng Y, Chen J, Zhao Y, Yan X, Zhang into plantar calluses, was presented fight against rare diseases. The L, Choy K, Hu J, Sant HJ, Gale BK, by Ofir Artzi. The trial plan was overall theme was 'Game changers Tang T. Transdermal Delivery of siRNA discussed followed by a discussion in Rare Disease - Delivering 21st through Microneedle Array.Sci Rep. of the pros and cons of various century healthcare to rare disease 2016 Feb 18;6:21422.

endpoints which might be used to patients: Together we can change Edwards KA, Terry SF, Gold D, Horn evaluate the trial. Ideas included a the future'. Approximately 800 par- EJ, Schwartz M, Stuart M, Vernon SD. standard pain scale, PC Quality of ticipants and over 80 speakers met Realizing Our Potential in Biobanking: Life questionnaire developed by to cover six themes of Game Disease Advocacy Organizations Enliv- Peter Hull, an activity monitor, pa- Changers - in research, diagnosis, en Translational Research. Biopreserv tient diary and clinical photo- drug development, authorisation & Biobank. 2016 Apr 8. graphs. access, care provision, social poli- Forrest CE, Casey G, Mordaunt DA, cy and in global society. As well as Thompson EM, Gordon L. Pachyonych- The final talks focussed on aspects individuals from Europe, there ia Congenita: A Spectrum of KRT6a of the nail. Campbell Stewart were also representatives from in- Mutations in Australian Patients. Pedi- shared the results of his study on dustry and patient groups from atr Dermatol. 2016 May;33(3):337-42. 'The histological features of the USA, China, India, South Africa, nail plate in PC' and Frances Smith New Zealand and Australia. Has C, Technau-Hafsi K. Palmoplantar presented findings on a retrospec- keratodermas: clinical and genetic as- pects. J Dtsch Dermatol Ges. 2016 tive study 'Nail removal as a PC Emphasis was placed on the strong Feb;14(2):123-39. treatment' followed by a discussion need for everyone to co-operate led by Albert Bravo and David and collaborate not just within Eu- Kerns ML, Hakim JM, Lu RG, Guo Y, Hansen. rope but globally to benefit all rare Berroth A, Kaspar RL, Coulombe PA. disease patients from diagnosis to Oxidative stress and dysfunctional The symposium ended with a re- care and treatment. Many examples NRF2 underlie pachyonychia congenita minder that the IPCRR data is 'A were given to show how with new phenotypes. J Clin Invest. 2016 Jun 1;126(6):2356-66. treasure trove of information on technologies it is easier to connect PC' and readily available to IPCC and build communities. There were Ni C, Yan M, Zhang J, Cheng R, Liang members for studies and articles. presentations and discussions about J, Deng D, Wang Z, Li M, Yao Z. A the European Reference Networks novel mutation in TRPV3 gene causes Following the main IPCC meeting (ERN) being set up to work across atypical familial Olmsted syndrome. Sci on May 11th, the IPCC Steering borders, across different jurisdic- Rep. 2016 Feb 23;6:21815. Committee and guests met for a tions etc to connect experts and Rathore PK, Khullar V, Das A. Pachy- brainstorming session focused on highly specialised services to serve onychia Congenita Type 1: Case Report clinical trial design. all rare disease patients. Feeding and Review of the Literature. Indian J into these discussions were two Dermatol. 2016 Mar-Apr;61(2):196-9. EUROPEAN CONFERENCE ON video presentations by members of NIH National Center for Advanc- Sakiyama T, Kubo A. Hereditary RARE DISEASES "clinical and The 8th European Conference on ing Translational Sciences (NCATS) in the USA. The opportunity to genetic differential diagnosis". J Derma- Rare Diseases & Orphan Products tol. 2016 Mar;43(3):264-74. was held in Edinburgh May 26-28, learn from each other so less ad- 2016. The aim of these conferences vanced regions in a given field can Tariq S, Schmitz ML, Kanjia MK. is to unite all rare disease stake- benefit from experience sharing Chronic Foot Pain due to Pachyonychia holders from all European nations - with other areas in Europe and Congenita in a Pediatric Patient: A Suc- globally will lead to more effective cessful Management Strategy. A Case patients and patient representa- Rep. 2016 May 15;6(10):305-7. tives, healthcare professionals and outcomes.

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ganized corneal epithelium with keratinopathies including Epider- KEEPING AN EYE cell fragility and rupture of epithe- molysis Bullosa Simplex and ON THE KERATINS lial cysts at the corneal surface Pachyonychia Congenita. were revealed. Interestingly, the K12-Leu132Pro mutation caused References: Emily Warshauer MD an altered keratin profile with up- Allen EH, Courtney DG, Atkinson Univ of Colorado regulation of KRT6, KRT16 and SD, Moore JE, Mairs L, Poulsen KRT14 consistent with the stress ET, Schiroli D, Maurizi E, Cole C, Eyesight is fundamental as one of response to compensate for de- Hickerson RP, James J, Mur- our five senses to see our sur- creased integrity of the cytoskele- gatroyd H, Smith FJ, MacEwen C, roundings. Vision involves our ton. In contrast to the human Enghild JJ, Nesbit MA, Leslie eyes working in coordination with MECD cornea, KRT5 expression Pedrioli DM, McLean WH, Moore our brain to interpret and interact is decreased in the mouse genome, CB. Keratin 12 missense mutation with the world around us. Critical hypothesized to be due to a lack of induces the unfolded protein re- thinking, scientific discovery and a KRT3 equivalent. sponse and apoptosis in Meesmann progress all require vision. epithelial corneal dystrophy. Hum Within the classical group of dom- Mol Genet. 2016 Mar 15. With our eyes on the keratins, a inant-negative genetic disorders, similar vision is required to more Meesmann epithelial corneal dys- Courtney DG, Atkinson SD, Allen completely understand the struc- trophy has been a focus for the de- EH, Moore JE, Walsh CP, Pedrioli ture and function of these . velopment of allele-specific thera- DM, MacEwen CJ, Pellegrini G, Keratin 3 (KRT3) and Keratin 12 peutic siRNA. In the 2011 publi- Maurizi E, Serafini C, Fantacci M, (KRT12) come to the forefront, cation of PloS One, Liao and col- Liao H, Irvine AD, McLean WH, both playing a special role in the leagues adapted the siRNA se- Moore CB. siRNA silencing of eye as cornea-specific keratins and quence walk methodology to de- the mutant keratin 12 allele in cor- implicated in corneal dystrophies. sign a potent siRNA against the neal limbal epithelial cells grown mutant allele K12-Leu132Pro. from patients with Meesmann's In the March 2016 issue of Human epithelial corneal dystrophy. In- Molecular Genetics, Allen and Furthermore, in the 2014 publica- vest Ophthalmol Vis Sci. 2014 colleagues sought to further inves- tion of Investigative Ophthalmolo- May 6. tigate the pathomechanism of gy & Visual Science, Courtney and Meesmann epithelial corneal dys- colleagues confirmed the siRNA Liao H, Irvine AD, Macewen CJ, trophy (MECD) and shed light on approach as a viable treatment op- Weed KH, Porter L, Corden LD, the eye-specific keratins. They tion within the context of an effec- Gibson AB, Moore JE, Smith FJ, generated and phenotypically char- tive delivery vehicle. McLean WH, Moore CB. acterized a knock-in humanized Development of allele-specific mouse model carrying the severe True vision is key to fully realize therapeutic siRNA in Meesmann MECD-associated K12-Leu132Pro the potential of RNA interference epithelial corneal dystrophy. PloS mutation. While no alterations in therapeutics for the prevention of One. 2011. corneal opacity were detected by Meesmann epithelial corneal dys- slit-lamp examination, disor- trophy in addition to other

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TOPICAL SIROLIMUS UPDATE 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 Wesley Kaupinen Roger Kaspar, Fragility Palvella Therapeutics TransDerm -DNA Repair Diseases -Ectodermal Dysplasias -Vascular Diseases (genetic origin We are pleased and excited to offi- ed an excellent safety profile: there cancer and clinical aspects) cially announce that topical siroli- were few local and systemic ad- Registration is free. For additional mus (TD201) for PC patients will verse events, no serious adverse information contact Fernando be advancing towards its next hu- events, and overall the topical siro- Larcher, PhD at man clinical study. TransDerm has limus cream was well tolerated. [email protected] recently partnered with Palvella Therapeutics, a Philadelphia-based The path forward for topical siroli- PC PROJECT TO HOST company focused on relentlessly mus in PC will now involve the and selflessly serving individuals Palvella and TransDerm teams MEETINGS IN MADRID AND suffering from rare diseases working closely together to build EDINBURGH IN OCT 2016 (Palvella, in Finnish, means “to upon the novel formulation devel- Following the Rare Disease con- serve”), to rapidly advance the oped at TransDerm and explore ference, PC Project will host a program. Palvella’s core compe- the potential to optimize that for- meeting for patients and research- tencies involve developing and mulation for the benefit of PC pa- ers in Madrid, Spain. Beginning commercializing novel rare dis- tients. Once that analysis is com- with a dinner on Friday, October ease therapies in the US, Europe, plete and the FDA has been 21 at the NH Nactional Hotel, pa- and other geographies. Many of properly engaged on the status and tients and researchers will enjoy you will have the opportunity to plans of the program, topical siro- presentations and discussion on hear more about Palvella and meet limus will be poised to enter its Saturday, October 22 from 9am to their leadership team in the months next clinical study, which will 4pm. If interested, please email to come. more thoroughly evaluate thera- [email protected] peutic efficacy. Consistent with the goals of any The 2016 PC Patient Support initial study of an experimental Thanks to all of you for your en- Meeting will be held in Edinburgh therapy in a rare disease, the Phase gagement over many years to ad- for patients and researchers. The Ib study of topical sirolimus eluci- vance this promising therapy for event begins with a dinner on Fri- dated several key learning points PC patients. Success going for- day, October 28 with presentations about the potential for this therapy ward will again necessitate the from major leaders in PC research in PC. The study met its primary same extraordinary level of collab- throughout the day on Saturday objective of demonstrating the oration, and we will again aim to and one-half day on Sunday. Reg- safety of topical administration of harness the collective wisdom and istration is required. If you are in- sirolimus cream for the treatment expertise to design and enroll the terested in attending, please email of painful plantar keratoderma in next clinical study. [email protected]. PC. Topical sirolimus demonstrat-

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- we have all shared over the last mance and AstraZeneca’s highly tering and atopic disease. years — to develop and deliver prestigious “Leadership Excellence J Allergy Clin Immunol. 2016 Jun effective treatments for PC patients Award” and "Global Challenge 15 — will move forward and be Award." She helped bring over 16 achieved under Cindy’s new pharmaceutical products to Rittié L, Farr EA, Orringer JS, leadership.” market. Early in her career, she Voorhees JJ, Fisher GJ. Reduced Cindy Byers Atha is a Healthcare was recognized by several key cell cohesiveness of outgrowths Executive with a 26-year history of healthcare clients as the best ac- from eccrine sweat glands delays Commercial experience in a series count representative in the indus- wound closure in elderly skin. Ag- of increasingly responsible Sales try. She gained formative experi- ing Cell. 2016 May 17 and Marketing roles at Atossa Ge- ence as an Account Executive with netics, Depomed, Inc., and Amylin Scientific Technologies, promoting Schiller SA, Seebode C, Wieser Pharmaceuticals, innovative bio- the sale of research and medical GL, Goebbels S, Ruhwedel T, Hor- tech/biopharmaceutical companies, equipment to leading biotechnolo- owitz M, Rapaport D, Sarig as well as AstraZeneca, one of the gy companies and medical centers. O,Sprecher E, Emmert S. Non- world’s leading pharmaceutical keratinocyte SNAP29 influences companies. She most recently was Ms. Atha also serves on the Board epidermal differentiation and hair the Vice President of Sales and of Directors for Operation of Hope, follicle formation in mice. Exp Marketing at Atossa Genetics a non-profit organization that pro- Dermatol. 2016 Aug;25(8):647-9 where she led commercialization vides facial reconstructive surger- efforts for pharmacogenomic test- ies to poor children around the ing and medical devices for Breast world. She is a member of the Health. Previously, she was Vice Academy of Managed Care Phar- President of Managed Markets and macy and a volunteer mentor for Trade with Depomed overseeing BoomStartup. She received her Managed Care Sales and Market- Bachelor of Science in Zoology ing, Pricing, Contracting, Trade, from North Carolina State Univer- and Distribution. While at sity in Raleigh, North Carolina. Depomed, her team was recog- She and her husband William re- nized by Healthcare Distribution side in Salt Lake City, UT. Management Association (HDMA) as 2014 DIANA Winner for Best Manufacturer and while perform- PC ADVOCATES TRAINING ing a similar role at Amylin, her Beginning with eight patients in team was twice recognized for the USA, PC Project has begun a “Best Marketing Programs and program to educate, inspire and Cindy Byers Atha People” for a small manufacturer involve patients as advocates in Executive Director and achieved the 2012 DIANA their own communities. Pachyonychia Congenita Project Award for best new product intro- PC PROJECT APPOINTS NEW duction. Ms. Atha began her phar- Ten patients from England, Fin- land, France, Germany, India, EXECUTIVE DIRECTOR maceutical career in field sales Spain, The Netherlands and Wales Staff members at PC Project (Mary with Merck & Co. and then moved are completing webmeeting train- Schwartz, Frances Smith and Holly to AstraZeneca where she ad- ing sessions and will meet in Edin- Evans) are thrilled to introduce the vanced into Senior Sales Leader- burgh just prior to the Patient Sup- new Executive Director for PC ship. She was the recipient of more port Meeting for an in-person train- Project to our IPCC members. than 16 sales awards for exception- ing session with IPCC leaders. Mary says “I am certain the goal al individual and group perfor-

2386 East Heritage Way, Ste B, Salt Lake City, UT 84109 · www.pachyonychia.org · Phone 877-628-7300 · Email: [email protected]