Update on pachyonychia congenita research

TY - JOUR

T1 - Update on pachyonychia congenita research

AU - Funk, T.

AU - Hansen, C. D.

AU - Paller, A.

AU - O'Toole, E. A.

N1 - Funding Information: T. Funk funkt@ohsu.edu C.D. Hansen A. Paller E.A. O'Toole Dermatology Oregon Health& Science University Portland OR 97239‐3098 U.S.A. Dermatology University of Utah Salt Lake City UT U.S.A. Northwestern University Feinberg School of Medicine Chicago IL U.S.A. Centre for Cell Biology and Cutaneous Research Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London London U.K Acknowledgments: the PC Project and speakers at the IPCC Symposium included Birgitte Lane, Pierre Coulombe, Christopher Bunick, Thomas Magin, David Kelsell, Robyn Hickerson, Michael Conneely, Michael Caterina, Edel O'Toole, Alain Hovnanian, Dennis Roop, Weston Daniel, Mark de Souza, Eugene Sullivan, Braham Shroot, John Doux, David Hansen and Janice Schwartz. Please see https://www.pachyonychia.org/2019ipcc/ for a full review of the 2019 IPCC meeting. Funding sources: none. Conflicts of interest: T.F. has been an investigator and consultant for Palvella Therapeutics, and is a Pachyonychia Congenita (PC) Project medical and scientific advisory board member. C.D.H. has been an investigator and consultant for Palvella Therapeutics, and is a PC Project medical and scientific advisory board member, and an International Pachyonychia Congenita Consortium (IPCC) steering committee member. A.P. has been an investigator and consultant for Palvella Therapeutics, and an advisor for Exicure. E.A.O.T. has been a consultant for Palvella Therapeutics and is a PC Project medical and scientific advisory board member and an IPCC steering committee member. Dear Editor , Pachyonychia congenita (PC) research is gathering pace, with a number of important recent advances supported by the International Pachyonychia Congenita Consortium (IPCC). Highlights from this year's IPCC Symposium include research presented by scientists studying keratin biology and structure, inflammation in PC and the latest advances in therapeutics, including keratin modification via existing chemical compounds, nucleic acid delivery and stem cell therapy. A Therefore, a possible therapeutic approach in PC might be the targeted upregulation of Krt16 null mouse model with a palmoplantar keratoderma (PPK) similar to that found in patients with PC has been developed to improve the study of the disease mechanisms underlying PC. In the mouse model, there is a dramatic loss of keratin 9 in the footpad skin keratinocytes. Krt9 null mice also develop calluses, indicating that keratin 9 is likely to be important in the development of PPK. Krt9 . Work with the Calluses in patients with PC‐K16 also show evidence of reduced Nrf2 activity, highlighting the inflammatory cascade in PPK as a target for therapeutic developments in PC. Krt16 null mouse model has also demonstrated that there is increased oxidative stress including reduced Keap1–Nrf2 signalling during the formation of PPK. The inflammatory response in PC is an active area of research. Maruthappu which may therefore have relevance in the study of PC. et al . have studied iRhom2 and the keratinocyte stress response in tylosis, a syndrome characterized by PPK and a high risk of developing oesophageal squamous cell carcinoma. The iRhom2 molecule functions as a major regulator of the response to cellular stress, including orchestration of keratin 16 dynamics, Researchers are hopeful that understanding the structural changes that occur in mutant keratin molecules will improve understanding of the PC disease process and may inform therapeutic options in the future. Atomic resolution structures have the ability to create ‘genotype–structurotype–phenotype’ models of disease. The first crystal structure of a keratin mutation associated with human skin disease has been created and highlights a critical knob‐pocket assembly mechanism within the K1 helix 1B domain, which is conserved among all type II keratins. Compounds that modify keratin post‐translationally are of interest in the possible treatment of PC and are currently being systematically evaluated. A compound that decreases aggregation of keratin in cells with the epidermolysis bullosa simplex‐associated K14R125C mutation by 50% has already been identified. Robyn Hickerson (University of Dundee, Dundee, U.K.) is working on the development of increased specificity of antisense oligonucleotides towards targeting a single‐nucleotide mutation in collaboration with Wave Life Sciences (Cambridge, MA, U.S.A.) and is at the forefront in advancing delivery strategies. Nucleic acid delivery has been an ongoing therapeutic strategy in PC. The use of small interfering (si)RNAs to target mutant keratin expression has previously been a focus of study. Intralesional injection has historically been required for delivery, given that the epidermal barrier precludes penetration of siRNA. However, pain associated with the injectable delivery method is a major problem. Spherical nucleic acids (SNAs) are nanoparticle constructs with dense radial arrangements of oligonucleotides. These nucleic acids readily penetrate epidermal cells in vitro and intact human skin The oligonucleotide component of SNAs can suppress or modify disease gene expression, which suggests promise in the treatment of genetic skin diseases, including PC, and offers an alternative nucleic acid delivery mechanism. in vivo . There are two means by which these genetically modified cells can be delivered. Dennis Roop (University of Colorado, Aurora, CO, U.S.A.) has partnered with Avita Medical (Valencia, CA, U.S.A.), a company that manufactures a method for spraying dissociated cells onto patients. This method has been used effectively to treat patients with burn injuries and may represent a plausible delivery mechanism for keratinocytes derived from gene‐edited iPSCs, which would obviate the need to develop sheets of skin for grafting. Induced pluripotent stem cells (iPSCs) have been studied as a treatment for recessive dystrophic epidermolysis bullosa. Reprogramming fibroblasts with modified mRNA and microRNA is a nonintegrative method of introducing genetic modifications in patients’ fibroblasts. The 2019 IPCC Symposium highlighted progress in the understanding of PC pathophysiology and advances in the translation of this scientific knowledge into therapeutic options for patients with PC. Highlighted research with the potential for therapeutic development includes targeting the inflammatory response in callus development and the suppression or modification of genetic expression via nucleic acid delivery or the introduction of iPSCs. These scientific discoveries move us closer to viable therapeutic options for patients with PC.

PY - 2020/3/1

Y1 - 2020/3/1

UR - http://www.scopus.com/inward/record.url?scp=85076921779&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076921779&partnerID=8YFLogxK

U2 - 10.1111/bjd.18630

DO - 10.1111/bjd.18630

M3 - Letter

C2 - 31648361

AN - SCOPUS:85076921779

SN - 0007-0963

VL - 182

SP - 788

EP - 789

JO - British Journal of Dermatology

JF - British Journal of Dermatology

IS - 3

ER -