Fighting for a cure. Connecting & helping patients. Empowering research. IPCC Newsletter Editor: Edel O’Toole, MB, PhD, FRCP, FRCPI Vol 15, No. 1 Jan-Feb-Mar 2018 PC PROJECT WORKING TOGETHER WHY IS THE SKIN OF OUR FOR PC PATIENTS PALMS AND SOLES SO MUCH THICKER? The PC Project continues to provide services to Dr Anissa Chikh, Dr Thivi patients with pachyonychia congenita. In this Maruthappu and Prof David P Kelsell, Centre for Cell newsletter, we update you on new developments at Biology and Cutaneous Research, Blizard Institute, PC Project including data from the patient registry, Queen Mary University of London, London new publications, a profile of Pierre Coulombe from our Medical and Scientific Advisory Board and an Keratinocyte hyperproliferation and inflammation are update on development of topical rapamycin as a common to many skin disorders such as psoriasis, treatment for PC. atopic eczema and palmoplantar keratodermas (PPKs) including Pachyonychia Congenita (PC). The The key programs of PC Project are: PPKs are characterised by different patterns of hyperproliferative thickening of the palms and soles, The IPCRR (patient registry) founded in 2004 it and can often exhibit painful callous formation. is one of the most important achievements of PC Previously, the Kelsell group showed that inherited Project with over 700 PC patients now enrolled dominant mutations in RHBDF2, the gene encoding in 47 countries. iRHOM2, are the genetic basis of the inherited syndrome Tylosis with Oesophageal Cancer (TOC) The International PC Consortium (IPCC) to characterised by the development of a painful encourage and support collaborative research keratoderma in childhood and a 95% likelihood of efforts to find a treatment for PC. developing Oesophageal cancer >65 years old. Newsletters both for patients and for the IPCC The group recently published their research in members to inform and unite these communities. Nature Communications 2017, and described an important role for iRHOM2 as a master regulator of Annual PC Patient Support Meetings (PSM) stress responses in skin. They identified that where patients meet, teach and support one iRHOM2 is a novel regulator of the cytoskeletal another and effectively defeat the overwhelming response to physical stress through its interaction loneliness caused by an ultra rare disease. with keratin 16 (K16) in humans and mice. This has important implications for PPKs, wound healing, Publications to continue to bring attention to PC Thivi Anissa David and explain the debilitating nature of this disorder, emphasize the need for treatment and highlight important research achievements. Pachyonychia.org website with accurate and current information on all things related to PC. PC Project wants to express its deep gratitude for each of you - our dear friends old and new. Thank you for all you do to help PC Project, PC Patients and in moving PC research forward. PO Box 17850, Holladay, UT 84117 · www.pachyonychia.org · 801-987-8758 · [email protected] Page 2 IPCC Newsletter Jan-Feb-Mar 2018 Vol 15, No 1 inflammatory skin disease and cancers. They Upon joining the faculty and setting my independent showed that iRHOM2 regulates thickening of the research program at Johns Hopkins University in footpad epidermis where TOC-associated iRHOM2 1992, I decided to focus my efforts on understanding is characterized by palmoplantar thickening, the properties and roles of keratins 6, 16, and 17 upregulates K16 with robust downregulation of its (K6, K16, K17). I made this choice because these type II keratin binding partner K6. In contrast, genes were known to be upregulated following iRHOM2 loss results in reduced K16 expression and tissue injury and also in chronic skin diseases such rhbdf2-/- mice have a thinner epidermis in the as psoriasis and cancer, and relatively little was footpad compared to control mice. These findings known about the associated significance. The shed light on a novel role for iRHOM2 in regulating discovery of mutations in those specific keratin the epithelial stress response and contribute to our genes as the underlying cause for pachyonychia understanding of the molecular mechanisms congenita, reported in 1995, alerted us to new and underlying hyperproliferation of the palmoplantar important ways with which we could study these epidermis in both physiological and disease states. genes and their protein products. Moreover, as PC can be caused by mutations in Keratin 6 and 16, it could be intriguing to determine Without a doubt the birth of the Pachyonychia the contribution of iRHOM2, and its interaction with Congenita Project, circa 2003, has had an enabling these particular keratins in the development of and powerful impact on our research directions and keratoderma in PC. efforts. The opportunity to interact with Mary Schwartz, with other researchers with a direct or References: Maruthappu T, Chikh A, Fell B, peripheral interest in PC, and most especially with Delaney PJ, Brooke MA, Levet C, Moncada-Pazos individuals who live with this condition has been and A, Ishida-Yamamoto A, Blaydon D, Waseem A, continues to be a very inspiring and rewarding Leigh IM, Freeman M, Kelsell DP. Rhomboid family experience. I am so impressed with the PC Project, member 2 regulates cytoskeletal stress-associated and am immensely grateful for the opportunity to be Keratin 16. Nat Commun. 2017 Jan 27;8:14174. part of it. doi: 10.1038/ncomms14174 UPDATE ON PC PROJECT AND PALVELLA’S EFFORTS TO RAPIDLY ADVANCE NOVEL, HIGH STRENGTH IPCC SPOTLIGHT: PIERRE COULOMBE, PHD OPICAL APAMYCIN TO ATIENTS G. Carl Huber Professor and Chair, Department of Cell T R PC P and Development Biology, University of Michigan Medical Wes Kaupinen, Palvella School, PC Project MSAB With the enthusiastic and ever- I grew up in Montréal, Canada and willing help of PC Project and am a first generation scientist. As a scientists and clinicians PhD graduate student at the worldwide, Palvella Therapeutics Université de Montréal I developed continues to make meaningful a passion for the biology of progress on its development of an epithelial tissues by studying the enhanced formulation of topical response of the pulmonary rapamycin to be evaluated in a apparatus to experimental injury. Phase 2/3 safety and efficacy For postdoctoral training I joined a study commencing in 2018. The study builds on the laboratory headed by Dr. Elaine Fuchs at the compelling scientific rationale of rapamycin in PC University of Chicago, Illinois, hoping to decipher the first elucidated by Dr. Roger Kaspar and the mechanisms of epithelial differentiation in the TransDerm team, as well as the early directional epidermis of the skin. While in Dr. Fuchs lab, I clinical evidence generated from the oral rapamycin contributed to a reverse genetics-style effort that study and multiple topical rapamycin studies in PC. resulted in the discovery of the first set of mutations This study will be the first properly designed and in a keratin gene, namely K14, as causative agents adequately powered study to evaluate the efficacy of for the rare disease epidermolysis bullosa simplex. topical rapamycin in pachyonychia congenita. PO Box 17850, Holladay, UT 84117 · www.pachyonychia.org · 801-987-8758 · [email protected] IPCC Newsletter Jan-Feb-Mar 2018 Vol 15, No 1 Page 3 While the TransDerm team discovered certain be most valuable to PC patients. We look forward to proposed direct mechanisms of action in keeping everyone updated on the exciting progress. pachyonychia congenita (Hickerson et al., Journal of Dermatological Science, 2009), further therapeutic Philip Gard, MBChB effects of rapamycin in PC are likely derived from its IPCC Steering Commit- tee Member and PC known anti-inflammatory properties (Weichhart et al, Project Medical and Nature Reviews, 2015) and anti-angiogenic Scientific Advisory properties (Guba et al, Nature Medicine, 2002), each Board Member of which are important given the documented Jonathan K. Wilkin, inflammation and hyper-neovascularization MD, Founding Director, Division of Dermatolo- (Polydefkis et al, Pain, 2016) which are likely major gy and Dental Prod- contributors to PC disease pathogenesis. Phil Jonathan ucts, FDA Palvella’s efforts over the last several months have been acutely focused on two areas: i) Development of a high strength and rigorously tested formulation UPCOMING PC & EB PL-PFDD MEETING of topical rapamycin that has product attributes that are acceptable to both PC patients and global PC Project will participate in an Externally-led regulatory authorities; and ii) Careful selection of Patient-Focused Drug Development Meeting (EL- efficacy outcomes measures, i.e. endpoints, for PFDD) with FDA officials. inclusion into the clinical study. Endpoint selection is by no means trivial for PC given the multi-factorial This FDA meeting will take place the morning of presentation of the disease as well as the scarcity of April 6, at the College Park Marriott Hotel in clinical studies in PC, i.e. limited precedent from Hyattsville, MD, near FDA headquarters. which to work. Palvella has recruited some of the Approximately 50-75 PC patients and caregivers will world’s leading clinical trial design experts, including share their voices through panel presentations, the former Director of the FDA’s Dermatology electronic polling and moderated audience Division, to help address this issue. The clinical discussions. (After a shared luncheon with PC relevance of a narrowed list of potential efficacy patients, EB and EBS patients will have a similar endpoints, many of which are designed to meeting in the afternoon.) objectively evaluate function and ambulation in PC, have now been validated through survey work The Patient’s voice has historically been absent from directly with PC patients. Next steps for Palvella the drug development process until a drug was include proper interactions with regulatory approved by the FDA or when a clinical trial was authorities before initiating the clinical study later this failing and the FDA wanted input from actual year. patients to understand the problem. Now, the FDA wants to hear patient voices at the beginning of the Thanks to everyone who has been a contributor to process and throughout.