Meeting Report from Frontiers in Ichthyosis Research

Leonard M. Milstone,¹ William B. Rizzo² and Jean R. Pickford³

Reprinted with permission from Journal of Investigative Dermatology (2011) 131, 279–282. doi:10.1038/jid.2010.338

 

Frontiers in Ichthyosis Research, an international meeting of investigators actively involved in research directly related to ichthyosis, was held in June 2010, immediately preceded the biannual family conference held by the Foundation for Ichthyosis and Related Skin Types, Inc.^TM (FIRST), an ichthyosis patient-support organization.* The meeting was designed to foster collaboration among investigators  and between patients and investigators. It was an opportunity for the most deeply engaged individuals to begin a dialogue about efficient and effective ways to utilize scarce resources to advance research in ichthyosis. Invited speakers were asked to present ongoing research and their perspectives on significant challenges and opportunities (see photo).

Frontiers in Ichthyosis Research Meeting Participants

Leonard Milstone (Yale University, New Haven, CT, USA) introduced the meeting, noting that it was held on the tenth anniversary of the announced completion of the Human Genome Project. The identification of genes associated with human disease was an important spin-off from that worldwide effort and the ichthyoses were no exception. In the past 20 years we have come to recognize that the ichthyosis phenotype can be attributed to an unexpectedly large number of genes, whose coded proteins have a broad array of functions. This new perspective demonstrates that no aspect of epidermal biology can be taken for granted. This new appreciation opens the door for renewed collaboration between basic scientists interested in epidermal biology and keratinization and those interested in ichthyosis.

Despite the rarity of the condition, the study of patients with ichthyosis has had a substantial impact in two areas: (i) fundamental discoveries about critical skin functions and (ii) development of treatments that also benefit patients with more common skin diseases. It is not unreasonable to anticipate that stimulation of research in ichthyosis will continue to impact the skin disease community in this fashion. The meeting was organized into five sessions with a mixture of formal presentations and lively discussion.

Frontiers in genetic diagnosis

The identification of genes that cause ichthyosis has fundamentally changed the way we think about  this group of diseases and about skin biology. Judith Fischer (Centre National de Genotypage, Evry, France) gave a comprehensive review of how positional cloning has been used in the past 20 years to identify disease-causing genes. She described how her group used 130 consanguineous families to identify seven new genes that cause autosomal recessive congenital ichthyosis (ARCI). When 500 additional ARCI patients were screened for those genes plus transglutaminase 1, 22% still had no identifiable mutations. She indicated that single-nucleotide polymorphism arrays and whole-exome sequencing will speed mutant gene identification and reduce cost. Eli Sprecher (Sourasky Medical Center, Tel Aviv, Israel) spoke about the identification of genes causing syndromic ichthyoses—CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma caused by mutation in SNAP29) and ANE (alopecia, neurologic defect, and endocrinopathies caused by mutation in RBM28). He indicated that “rare is common” when looking for new disease genes in geographically, ethnically, or politically isolated populations and suggested that this approach will continue to be important in identifying proteins with critical functions in epidermis.

Keith Choate (Yale University) reported on a group of patients with ichthyosis for whom he and  Leonard Milstone collected data; the key questions for this group was not what caused the ichthyosis but what caused the areas of normal-appearing skin. He demonstrated that the normal skin resulted  from frequent, unique, somatic recombination events in keratinocytes and indicated how those independent somatic cell events were used to localize and identify the gene for ichthyosis with confetti. Amy Paller (Northwestern University, Chicago, IL, USA) concluded with a provocative review of the pros and cons of giving all patients with ichthyosis a genetic diagnosis. She noted that genetic diagnosis will change the way we think about classification, pathogenesis, prognosis, and therapy. Currently, the cost for making genetic diagnosis widely available in the United States is prohibitive.

Frontiers in understanding pathogenesis

As important and satisfying as it has been to learn about the genes and proteins associated with  ichthyosis, we are still quite ignorant, in many cases, about normal protein functions or what precisely goes wrong in a cell with a mutant protein. William Rizzo (University of Nebraska, Omaha, NE, USA)  gave a critical overview of lipid synthetic pathways in epidermis. For each enzyme defect known to be associated with ichthyosis, he revealed our inability to explain adequately all the clinical manifestations or to understand whether pathogenesis moved through substrate accumulation or product deficiency.   In the mouse model of Sjögren–Larsson syndrome that he created, he unexpectedly identified enzyme redundancy in mice but not in humans. Equally unexpected was the observation that the deleted gene resulted in substantially different phenotypes depending on the mouse strain—providing an opportunity to identify disease-modifying genes. Mason Freeman and Michael Fitzgerald (Harvard University, Boston, MA, USA) have created mouse models of mutant ATP-binding cassette A3 and A12 (ABCA3 and ABCA12). Fitzgerald explained the ways in which these mouse models of deficiencies in related lipid transporters differ from each other and how they have been useful in understanding the respective human deficiencies—neonatal respiratory distress syndrome and Harlequin ichthyosis— but also why they have been disappointing in elucidating disease pathogenesis completely. He suggested that mass spectroscopic analysis of lipids in this and similar monogenic epidermal diseases could lead to new therapeutic strategies.

Peter Elias (University of California, San Francisco, CA, USA) noted that ichthyosis therapy had often simply focused on scale removal. He urged the audience to consider pathogenesisbased therapy for ichthyotic epidermis caused by defects in lipid synthesis and delivery pathways. Such an approach  might employ both pathway inhibitors to reduce toxic lipid metabolites and lipid replacement to restoredeficient products. Hiroshi Shimizu (Hokkaido University, Sapporo, Japan) spoke about his experience with skin cancer occurring in unusual anatomic locations in patients with ichthyosis. He noted that  increased risk for skin cancer is accepted in Kindler syndrome, xeroderma pigmentosum, and recessive dystrophic epidermolysis bullosa, but that there are only a few anecdotal reports of cancer in ichthyosis. In general, we know little about the natural history of patients with ichthyosis, their relative lifetime risk for cancer or, if the risk is greater than normal, how the mutant gene might increase risk.

Alain Hovnanian (University of Paris, France) spoke about multiple effects of mutations in the gene for  the serine protease inhibitor, Kazal-type 5 (SPINK5), the cause of Netherton syndrome. The protein product of SPINK5—lymphoepithelial Kazal-type 5, or LEKTI—inhibits protease activity in the  epidermis, and he described molecular pathways by which LEKTI deficiency could lead to allergy and inflammation, as well as to its more obvious role in desquamation. Identifying the specific enzyme(s) inhibited by LEKTI could lead to development of small-molecule enzyme inhibitors, an area of active research in his lab. Pierre Coulombe (Johns Hopkins University, Baltimore, MD, USA) reviewed the well-accepted structural function of keratins in resisting shear stress and then provided less well-appreciated examples of keratin’s roles in signaling activity. As examples he mentioned the roles of K5 and K14 in pigment transfer from melanocytes to keratinocytes and of K17 in modulating patched pathway-mediated tumorigenesis and in Th1/Th2 immune balance in epidermis.

Frontiers in shared reagents and resources

Investigative communities are dependent on widely accepted tools, valid measures of events, and outcomes that interest them. Few such tools exist or have been widely applied to research in ichthyosis. If translational research in ichthyosis is to move forward, such tools must be devised and validated. Mary Williams (University of California, San Francisco) introduced this session by noting the major issues faced by those with ichthyosis: impaired barrier function and increased scale. She reviewed and critiqued the various physical and chemical methods currently employed to assess these issues. She described capabilities of additional physical measurements, such as ultrasound, confocal microscopy, Raman spectroscopy, and optical coherence tomography, which have yet to be applied to ichthyosis. Transepidermal water loss, hydration, and pH are measurements commonly employed in clinical and laboratory studies, but they have not been widely used in patients with well-characterized ichthyosis.

Roger Kaspar (Transderm, Inc., Santa Cruz, CA, USA) spoke about his recent experience developing a small interfering RNA (siRNA) to treat pachyonychia congenita. Severe pain upon intralesional delivery of the siRNA to a single patient precluded its continued use in that manner. However, that problematic experience spawned a collaborative effort to develop relevant, reproducible, widely available test systems to identify and optimize “patient-friendly” delivery of therapeutic nucleic acids to human epidermis. Dr. Kaspar acknowledged the key role played by the patient support group, PC Project, in pushing the clinical trial forward and promoting a collaborative atmosphere. Robert Rice (University of California, Davis, CA, USA) posited that the cornified envelope could be viewed as a snapshot of the health of the upper layer of epidermis at the time it is formed and that different diseases of epidermis might have distinct peptide signatures retained in the cornified envelope. He showed preliminary mass spectroscopic data demonstrating reproducibility of peptide signatures from

cornified envelopes collected from normal skin, and he showed some differences in envelopes collected from patients with ichthyosis, emphasizing that further work is needed to understand the significance of the findings.

Dennis Roop (University of Colorado, Aurora, CO, USA) spoke about the promise and practicality of using a patient’s keratinocytes to produce induced pluripotent stem (iPS) cells that might be used to treat genetic skin disease. He described his recent success in generating iPS cells from a patient with epidermolytic ichthyosis, which was supported by a grant from FIRST. He then explained that his future goal was to correct the genetic defect in these iPS cells and then differentiate them back into keratinocytes that could ultimately be returned to the patient as an autograft. A frank discussion of obstacles impeding translation of this technology into patient treatment ensued. Suephy Chen (Emory University, Atlanta, GA, USA) presented recent work creating and validating an ichthyosis clinical severity index for several types of ichthyosis. She indicated that some of the measures that clinicians have used routinely to rate severity of ichthyosis are not necessarily the measures that ichthyosis patients feel have the greatest impact on quality of life, hair loss being a specific example. She explained how improvements can be made in the tool she devised.

Frontiers in preparing for clinical trials

The conference was sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institutes of Health (NIH) Office of Rare Diseases (1R13AR059533-01) and by FIRST. The content is solely the  responsibility of the authors and does not necessarily represent the official views of the NIAMS or the NIH. Nine of the 18 speakers have received research support from FIRST. We thank Ellen B. Milstone for assistance in preparing this summary. Ambassadors from FIRST who participated in the final day of discussion included Joe Andrews; Wendy, Mark, and Tyler Breen; Mark and Cora Dunkin; Holly Friddle; Diana Gilbert; Angela Godby; John, Shannon, and Lauren Hamill; Mark, Kelly, and Adam Klafter; Randy LaBarbera; Ryan Licursi; Janet and Maggie McCoy; Laura Phillips; John Schoendorf; David Scholl; Brian See; and Hunter Steinitz.
 

Thanks to our meeting co-sponsors