2025 IPCC Symposium

8:00 – 8:10 am

Welcome Remarks by Pierre Coulombe, PhD, chair of the PC Project Research Committee

8:10 – 8:30 am

Janice Schwartz, BA

Executive Director, Pachyonychia Congenita Project

Janice Schwartz received a B.A. in communications with an emphasis in advertising from Brigham Young University. She raised four children (two who have PC), was a founding member of PC Project, and has served as a patient advocate for over 20 years. In 2017, Janice became the Executive Director and donates her time and efforts to continue the mission to help and support patients and to find effective treatments and a cure for those who suffer with PC and other rare, genetic skin diseases with painful palmoplantar keratoderma. Although she was first motivated to help her own children with PC, she quickly became driven by love for her other ‘children’ of all ages throughout the world who deal with these debilitating conditions.

New challenges, new opportunities, and the patients we serve

8:30 – 9:00 am

Eli Sprecher, MD, PhD, MBA

CEO, The Tel Aviv Sourasky Medical Center (Ichilov); Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel

Eli Sprecher is CEO of the Tel Aviv Sourasky Medical Center where he previously chaired the Division of Dermatology and served as Deputy Director for Patient Safety and Deputy Director for Research and Development. He is Frederick Reiss Professor of Dermatology at the Faculty of Medicine, Tel Aviv University and is past-president of the European Society for Dermatological Research (ESDR).
He received an MD degree from the Hebrew University, a PhD degree in Molecular Virology from the Hebrew University and an MBA degree from Tel Aviv University, and also spent a post-doctoral fellowship in Human Genetics at the Thomas Jefferson University, Philadelphia.
He has co-authored over 400 scientific publications and has earned several patents. He has mentored over 110 students and residents. His research focuses on the genetic basis of skin diseases. His group aims at understanding the molecular genetics of both simple and complex traits, deciphering their pathogenesis and then attempting at translating this new knowledge into innovative therapeutic tools.
Contact: elisp@tlvmc.gov.il

Palmoplantar keratodermas: one step forward

9:00 – 9:15 am

Benjamin A. Nanes, MD, PhD

Assistant Professor, Department of Dermatology and Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center

Dr. Nanes is a dermatologist and researcher at UT Southwestern Medical Center. He studies how the intermediate filament cytoskeleton organizes cellular signal transduction, coordinating tissue structure and function in contexts such as skin development, wound healing, and cancer. Dr. Nanes completed his MD and PhD at Emory University, followed by dermatology residency training and a postdoctoral fellowship in systems biology at UT Southwestern.

Distinguishing mechanical and non-mechanical functions of intermediate filaments

The keratin intermediate filament cytoskeleton provides critical mechanical support to the epidermis. Mutations in keratin genes that disrupt the intermediate filament network cause epidermal fragility in inherited skin diseases including pachyonychia congenita. However, the large number of keratin genes and their context-dependent expression pattern suggest that individual keratins might have additional more complicated roles. We recently identified a myosin-activating signaling circuit triggered by increased expression of keratin 6A, a pachyonychia congenita-associated keratin. We now report the mechanism underlying this signal transduction pathway, an isoform-specific interaction between keratin 6A and non-filamentous small oligomers of vimentin, the principal intermediate filament protein in mesenchymal cells. Rather than forming filaments, soluble vimentin acts as a signaling shuttle, delivering regulatory kinases into transient signaling complexes with myosin organized on keratin 6A-containing filaments. This pathway demonstrates how isoform-specific interactions and previously overlooked soluble pools allow intermediate filaments to organize cellular signals in parallel to their canonical role as mechanical scaffolds. However, whether disruption of keratin-organized signaling circuits contributes to the pathophysiology of pachyonychia congenita and other keratin-associated disorders remains unclear.

9:15 – 9:30 am

Keith Choate MD, PhD

Yale University

Keith Choate M.D., Ph.D., is the Aaron B. and Marguerite Lerner Professor and Chair of Dermatology, Associate Dean for Physician-Scientist Development, and Professor of Genetics and Pathology. A graduate of Stanford University and Yale’s Medical Scientist Training Program, Dr. Choate leads a translational research program in genetic skin disease. He studies rare inherited and mosaic skin disorders to reveal novel biologic pathways for epidermal differentiation and development, cellular competition, and neoplasia. Work in his laboratory has led to the development of pathogenesis-based therapies now employed in clinical practice. Dr. Choate in an active clinician in outpatient and inpatient dermatology, and he directs one of the largest international registries for patients in genetic skin disease. He is a Director of the American Board of Dermatology, President-Elect of the Pediatric Dermatology Research Alliance, and an active reviewer in NIH and extramural study sections.

Autosomal dominant SLURP1 damaging variants cause PPK and PSEK

Epidermal differentiation disorders (EDDs) are severe skin conditions characterized by localized or generalized skin scaling and erythema often due to damaging single-gene variants. We performed whole exome sequencing in a large cohort with EDD including palmoplantar keratoderma (PPK) and progressive symmetric erythrokeratoderma (PSEK)phenotypes to identify novel genetic variants. We investigated the consequence of these variants using in silico predictions, assays in primary patient keratinocytes, and high-resolution spatial transcriptomics and quantitative cytokine profiling in affected skin. We identified three unrelated kindreds with autosomal dominant transmission of heterozygous variants in SLURP1 at the same amino acid position (c.65C>A, p.A22D, and c.65C>T, p.A22V) within the signal peptide sequence. One (p.A22V) had isolated PPK, and two others (p.A22D) had a PSEK phenotype. In silico modeling suggested that variants altered the cleavage site of pro-SLURP1, appending two amino acids to the secreted protein, subsequently confirmed with mass spectrometry of secreted mutant protein. Assays in primary patient keratinocytes revealed that differentiation-induced SLURP1 expression and secretion was increased in patient cells compared to healthy control cells. Spatial transcriptomics in affected tissue confirmed increased SLURP1 expression in suprabasal epidermis and showed increased NF-κBsignaling and innate immune activity. Our results expand the phenotypic spectrum of EDD due to pathogenic variants in SLURP1.

9:30 -9:45 am

Cory L. Simpson, MD, PhD, FAAD

Assistant Professor, Department of Dermatology, University of Washington

Dr. Simpson is an Assistant Professor of Dermatology at the University of Washington. He earned his MD/PhD from Northwestern University in Chicago and studied the targeting of cadherins in skin blistering diseases, leading him to pursue dermatology residency at the University of Pennsylvania. After clinical training, he completed a postdoc to apply gene editing and live microscopy to organotypic human epidermis. In Seattle, his clinic focuses on blistering disorders while his lab is optimizing models of epidermal fragility disorders to find novel therapies.

A human epidermal model of keratin 5 loss-of-function reveals potential therapeutic strategies for epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) primarily causes painful blistering due to shearing of basal keratinocytes in the epidermis but can also lead to palmoplantar keratoderma. While this inherited skin fragility disorder was linked to mutations in the basal layer keratin (KRT) genes KRT5 and KRT14 more than 30 years ago, there are still no FDA-approved therapies for this congenital disease and treatments are focused on wound care, pain, and secondary infections. Krt5 knockout (KO) led to peri-natal death in mice, which has limited pre-clinical studies of EBS pathogenesis and interventions. We engineered a new in vitro human model to determine how KRT5 loss-of-function compromises epidermal integrity and to identify druggable disease modifiers in EBS. Using CRISPR/Cas9, we generated TERT-immortalized KRT5-deficient human keratinocytes, which we then grew as organotypic epidermis. KRT5-deficient cultures exhibited weakened intercellular junctions and altered differentiation markers. In organotypic epidermis, KRT5 KO cells exhibited basal keratinocyte fragility similar to EBS pathology. Intriguingly, some KO lines (KO-comp) exhibited compensatory hyper-differentiation with rescue of basal layer integrity. To elucidate potential pathogenic drivers and treatment strategies for EBS, we utilized RNA sequencing of both KO and KO-comp cell lines, which revealed differential expression of key regulators of KRT expression, epidermal differentiation, and cytokine signaling. Together, our data confirm that KRT5 loss-of-function compromises epidermal integrity but also can trigger compensatory cellular responses that may represent new targets for EBS therapeutics.

9:45 – 10:00 am

Pierre A. Coulombe, PhD

G. Carl Huber Professor and Chair, Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI

Pierre has been serving as professor and chair of the Department of Cell & Developmental Biology at the University of Michigan Medical School since 2017. Up until then, Pierre had been on faculty at the Johns Hopkins University in Baltimore, Maryland, where he held numerous leadership roles. Pierre’s primary passion is for epithelial biology – efforts in his laboratory are focused on defining the properties and roles of keratin proteins in normal healthy skin and their alterations in the setting of various types of skin diseases. Pierre has been associated with the Pachyonychia Congenita Project since its inception >20 years ago, and currently leads the research committee in the PC project. Pierre also enjoys mentoring aspiring scientists and health professionals.

K16 and K17 exert opposite influences on the skin’s response to stress

The keratins that give rise to Pachyonychia Congenita, when mutated, have the distinct property of being highly sensitive to various forms of stress. Research over the years in the Coulombe lab and elsewhere has shown that these keratins, K16 and K17 in particular, are intimately connected to inflammatory and innate immune responses in skin epithelia. Though K16 and K17 have both been implicated as causative factors in PC and as modifying factors in chronic inflammatory skin disorders (e.g., psoriasis), emerging evidence suggest that these two highly homologous proteins regulate stress responses in a strikingly distinct fashion in keratinocytes of the epidermis. The implications of the latest findings relevant to K16 and K17 for PC will be discussed at the meeting.

10:15 – 10:30 am

Michael J. Caterina, MD, PhD

Professor of Neurosurgery, Director of the Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine

After earning MD and PhD degrees from Johns Hopkins School of Medicine, Michael Caterina carried out a postdoctoral fellowship at The University of California, San Francisco, where he identified TRPV1, an ion channel receptor that mediates both the pain caused by hot chili peppers and the pain caused by high temperatures. As a faculty member at Johns Hopkins School of Medicine, he has continued to study the molecular and cellular mechanisms that lead to pathological pain. His lab is currently focused on mechanisms driving pain in hereditary skin diseases, on the mechanisms by which peripheral nerve injury leads to neuropathic pain, and on the development of novel genetic strategies to treat pain.

Probing mechanism of pain in mouse models of palmoplantar keratodermas

Pain is among the most impactful symptoms of some hereditary palmoplantar keratodermas. Yet, treatments for PPK-associated pain are limited and often ineffective. We are utilizing mouse genetic models of human hereditary PPKs to identify the cellular and molecular drivers of such pain. We have found that SLURP1 and SLURP2 knockout mice, genetic models of human Mal de Meleda, uniformly exhibit painful PPK, characterized by exaggerated evoked and spontaneous pain behaviors, neuronal hyperexcitability, palmoplantar immune cell changes, alterations in skin neuroanatomy, and changes in gene expression in the sensory ganglia innervating PPK-affected skin. We are currently evaluating the functional significance of these gene expression changes as potential drivers of PPK-associated pain.

10:30 – 10:45 am

Diana M. Bautista, PhD

HHMI Investigator & Professor, Department of Molecular & Cell Biology, UC Berkeley

Dr. Diana Bautista is an HHMI investigator, Professor, and Head of the Cell Biology, Development & Physiology Division in the Department of Molecular and Cell Biology at the University of California, Berkeley. She was a postdoctoral fellow with Dr. David Julius at the University of California, San Francisco where she demonstrated critical roles for the cold-sensitive ion channel TRPM8 and the irritant receptor TRPA1 in transducing temperature, pain, and neurogenic inflammation. She joined the faculty at UC Berkeley in 2008, where her lab aims to decipher the neuroimmune interactions driving chronic itch, pain, and airway inflammation associated with injury, disease and infection.

Neuroimmune mechanisms of itch and pain in atopic dermatitis

Atopic dermatitis is a highly prevalent chronic itch disorder with limited treatment options. In addition to severe and persistent itch sensations, a significant percentage of atopic individuals also experience pain. Aberrant activity of epithelial cells, neurons and immune cells is a hallmark of atopic dermatitis, but the fundamental molecular and cellular interactions that trigger the transition from acute itch to chronic itch, and the development skin pain remain largely unknown. This talk will highlight the interactions between diverse cell types in the skin that drive the development of neuronal hyperexcitability, itch, pain and inflammation.

10:45 – 11:00 am

Amanda M. Nelson, PhD

Associate Professor of Dermatology
Penn State College of Medicine

Amanda Nelson, PhD, is an Associate Professor of Dermatology at the Pennsylvania State University College of Medicine in Hershey, PA. Dr. Nelson received her PhD from Pennsylvania State University College of Medicine and completed two postdoctoral research fellowships in dermatology at Penn State and at Johns Hopkins University where she expanded her expertise in sebaceous glands, hair follicles, skin stem cells and wound healing. Areas of Expertise: translational research, inflammatory skin diseases (acne vulgaris, hidradenitis suppurativa), skin microbiome, wound healing, epithelial biology.

Hidradenitis suppurativa: bed to bench to bedside

Hidradenitis Suppurativa (HS) is a chronic, debilitating, inflammatory skin disease affecting skin folds that often results in permanent scarring. The pathogenesis of HS is unclear. Our lab takes a “Bed to Bench to Bedside” approach, working in collaboration with patients, clinicians and bioinformaticians, to understand inflammatory mechanisms in HS. Working with industry partners, we aim to identify and test new therapies for HS.

11:00 – 11:15 am

Marta Garcia Diez, PhD

Bioengineering Department, Universidad Carlos III de Madrid (UC3M); Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT); Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER-ISCIII); Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain

Ph.D. in Biochemistry and Molecular and Cellular Biology. Her research career has focused on the study of the molecular and cellular biology of the skin and more recently on the development of advanced therapies for the treatment of genetic skin diseases with a translational approach of the technologies developed towards the clinic. To this end, she has been involved in the development of several platforms to study the molecular genetics and mechanisms of skin diseases. Using the humanized mouse model system based on tissue engineering, she has participated in the modeling of a number of acquired and genetic skin diseases. Among the latter: Epidermolysis Bullosa (EB), Xeroderma Pigmentosa (XP) and Pachyonychia Congenita (PC). These models allow the acquisition of fundamental knowledge about the mechanisms involved in the different pathologies, becoming an important tool for the development of new therapeutic approaches (both cellular, genetic and pharmacological) and for carrying out various preclinical studies in vivo. In 2011, she was hired by the Carlos III University of Madrid to help launch a new degree program in Biomedical Engineering at the university, with which she continues to be linked since then as an associate professor.

Establishment of preclinical therapeutic protocols by in vivo inactivation of the pathogenic allele in KRT6A using CRISPR/Cas12

Pachyonychia Congenita (PC) remains without a curative treatment and management is mainly focused on symptom control, especially pain relief. In previous work, we developed a disease model using patient-derived cells carrying the dominant negative mutation p.Asn171Lys in KRT6A, recapitulating the hyperproliferative phenotype in a humanized murine skin model [Garcia, M., et al. J Invest Dermatol, 2011]. The most promising therapeutic approach in the context of gene therapy for PC must focus on the inactivation of the pathogenic allele due to its dominant negative effect on the healthy allele. Therefore, conventional strategies based on the addition of a functional copy of the gene are not effective. The recent development of gene editing technologies, in particular CRISPR/Cas, allows the exploration of gene therapy protocols aimed at inactivating the mutant allele.
We found that the c.513C>A (p.Asn171Lys) mutation in KRT6A creates an exclusive PAM site for the Cpf1/Cas12 nuclease (VTTT). We designed a complementary RNA guide to the sequence adjacent to this PAM and evaluated its efficacy and allele specificity in vitro. Our results show that electroporation of this guide as a ribonucleoprotein (RNP)-CRISPR/Cas12 complex into patient-derived keratinocytes efficiently and specifically disrupts the pathogenic allele and restores intermediate filament cytoskeletal organization. Since genetically corrected skin grafts are not a viable option for PC, the therapeutic approach must focus on in vivo interventions. We are currently developing vectors for effective delivery of CRISPR/Cas12 to the basal layer of the epidermis, where epidermal stem cells reside. This is being accomplished using both viral and non-viral vectors. We have performed a preliminary evaluation of the efficiency and specificity of this system in patient cells in vitro, and in the next phase we plan to validate these vectors in the mouse model previously established by our group.

11:15 – 11:30 am

Joshua Tam, PhD

Assistant Professor of Dermatology, Wellman Center for Photomedicine, Massachusetts General Hospital, Affiliate Faculty, Harvard-MIT Health Sciences and Technology

Josh Tam is a biomedical engineer at the Wellman Center for Photomedicine, Massachusetts General Hospital. Most of his work has been on medical devices, including as a co-founder of a startup company that developed a skin grafting device based on technology that he co-invented. He was also a key contributor in the development of fractional laser-assisted drug delivery. His recent research is focused on the specialized physiology of plantar skin.

Challenges and strategies for drug delivery into the plantar epidermis

All potential therapies for PC, from traditional drug molecules to advanced gene-editing approaches, must eventually confront what has long been a critical roadblock hampering the development of PC therapies: delivery of the therapeutic agents into the plantar epidermis. The structural and biochemical properties of the plantar epidermis are highly specialized for weightbearing, and pose unique obstacles to drug delivery that are generally not addressed by existing drug delivery technologies. This presentation will focus on specific challenges to drug delivery in plantar skin, and our recent work to overcome these challenges.

11:30 -11:45 am

Karen McGuire, PhD, CEO

Chief Executive Officer and Co-Founder of BioMendics, LLC

Dr. McGuire is the CEO and Co-Founder of BioMendics and is responsible for the company’s research and development and the clinical development of its lead small molecule MTORX(TM) technology and lead topical formulation known as TolaSure(TM). Dr. McGuire has a degree in Biomedical Engineering from the University of Toledo and a doctorate in Cellular and Molecular Biology from Kent State University’s School of Biomedical Sciences. She has 20 years of experience in the drug development field with a broad background in designing new pharmaceuticals, drug formulations and clinical trials. She is very excited to work with both PC Project and debra of America to find treatments for both of these keratin linked genetic skin conditions.

Autophagy induction as a new therapeutic target for pachyonychia congenita

Introduction: Pachyonychia Congenita (PC) is an ultrarare dermatologic disorder affecting an estimated 10,000 people worldwide. PC is caused by an autosomal dominant mutation in a series of keratin genes (KRT6A/B/C, KRT16, & KRT17). PC manifests with blisters, ichthyosis, deformed, thickened, or discolored nails and constant plantar pain. Plantar pain has the greatest impact on quality of life. PC is an unmet need with no approved therapies. PC and epidermolysis bullosa simplex (EBS) are caused by mutated keratins that form structurally weakened keratin intermediate filaments (KIFs). Stress collapses the KIFs into aggregates weakening the suprabasal keratinocytes causing premature cell death which contributes to ichthyosis. Clinical trials for oral rapamycin were not well-tolerated. Topical rapamycin trials did not reach significance. Our research suggests a potential benefit of autophagy induction by mTOR inhibitors to treat EBS. The purpose of this research was to evaluate mTOR inhibitors including BM-3103 (4-Hydroxy 4′-methyoxytolan) and rapamycin in vitro in PC keratinocytes. Specific aims: 1) autophagy induction, 2) KIF stability, 3) uptake of keratin by the autophagosome. Methods: In vitro analysis was performed using immortalized cell lines (K6a N171K, K16, N125D) derived from PC patients. Autophagy signaling was evaluated using western blotting and immunocytochemistry. A heat stress assay was used to assess KIF aggregation. Colocalization using immunofluorescence of keratin (K6a/K16) uptake by the autophagosome (LC3-II) was done. Results: At 25uM BM-3103 was significantly better than rapamycin at inducing autophagy(p=0.03). BM3103 increased LC3-II levels 5-12-fold vs 0.5-1.6-fold for rapamycin (0.4μM). BM-3103 treated cells resisted KIF collapse after heat stress. Keratin was colocalized with LC3-II staining of autophagosomes. Conclusions: Induction of autophagy in PC cells increasing KIF network stability through the degradation of mutant and damaged keratins. mTOR inhibitors like BM-3103 need to be clinically tested to assess impact on blistering and ichthyosis. McGuire, K., Rowe, T., Broadwater, L., and McCormick, A. BioMendics, LLC 4209 State Route 44, Rootstown, OH 44272

11:45 – 12:00 pm

David Aviezer, PhD, MBA

CEO of Kamari Pharma; Associate Professor, Biotechnology Dept., Bar Ilan University.

David Aviezer has 25 years of experience in biotechnology executive management, advancing biopharmaceutical drugs focused in the rare disease field, from early-stage research through their approval by the FDA. He was CEO of Protalix Biotherapeutics for 12 years and a visiting scientist at Wyeth-Pfizer. He has experience in creating strategic partnerships and research agreements and has raised significant capital on Wall Street. David is an Associate Professor and adjunct at the Faculty of Life Sciences at Bar-Ilan University. David currently serves as CEO of Kamari Pharma, a biotechnology company focused on rare genetic skin disorders. He holds a Ph.D. in Molecular Biology and Biochemistry from the Weizmann Institute of Science, Israel, and an M.B.A. from Bar-Ilan University.

TRPV3 inhibitors: a novel investigational treatment of PC, Olmsted syndrome and other keratoderma patients

TRPV3 plays a central role in skin disease as it regulates the proliferation, differentiation, and barrier function of human skin. KM-001 and KM-023 are specific and selective TRPV3 small molecule inhibitors that address both molecular and local damage to the skin by regulating Ca²⁺ influx into the cell, thereby reconstructing the skin barrier and reducing pain and inflammation. Kamari Pharma is developing KM-001 for the topical treatment of palmoplantar keratoderma, including Pachyonychia Congenita, and KM-023 for the Oral treatment of Olmstead syndrome, severe keratoderma, and Ichthyosis. Pre-clinical and clinical data will be discussed.

12:00 – 1:30 pm

Collaborating for success: harnessing collective expertise

Working lunch with full group discussion

Moderators: Pierre, Eli, Robyn, Alain, David
Special guests: Peter Koch, Alexey Belkin (NIAMS)
All attendees are invited to participate and add their insights and knowledge to the discussion.

1:30 pm Final remarks: call to action