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American Diabetes Association

Conference summaries


Epidermolysis bullosa

New start of gene therapy in epidermolysis bullosa

Presented by: Prof. Leena K. Bruckner-Tuderman University Medical Center, Albert-Ludwigs-University of Freiburg, Germany
  • Ex vivo gene therapy of EB has been successively demonstrated by several proof-of-principle investigations.
  • In the future, gene therapy of EB is likely to be able to provide full functional correction of the disease.

Epidermolysis bullosa (EB) is a major, rare disease of the skin that in extreme cases can be fatal. The symptoms of EB are life-long and include mechanically-induced blistering, chronic wounds, perturbed wound healing, pain, secondary infections, alopecia, loss of nails, scarring and fibrosis. The disease manifests with a very broad spectrum of severity and presentations. The main subtypes comprise simplex EB, junctional EB, dystrophic EB and kindler EB. To date pathogenetic variants have been recognised in >20 genes. The severe forms have a very high unmet medical need, and evidence-based therapies are urgently needed.

  • Accurate diagnosis of EB is not only important for treatment, but is also a prerequisite for participation in clinical therapeutic trials.
  • In addition to clinical presentation and family history, genetic analysis can be carried out on single gene if there is a clear candidate gene, or in a gene panel.
  • For cases which are not possible to classify, exome sequencing can be utilised.
  • All these techniques can lead to accurate diagnosis.
  • As with other genetic diseases, a number of new approaches to treatment are under investigation.
  • These include curative approaches (e.g. gene therapy, protein and RNA-based therapies), regenerative approaches (use of somatic cells, mesenchymal stem cells, bone marrow transplantation) and disease modifying approaches (small molecules and biologicals).
  • Among these, ex vivo keratinocyte gene therapy has been used for EB for more than 13 years.
  • In this technique, cultured keratinocyte stem cells, known as holoclones, generate sheets of epithelium used to restore severe skin defects.
  • In a recent investigation, topical and intradermal gentamicin was shown to suppress nonsense mutations and induces type VII collagen and anchoring fibrils in EB patients.
  • Gentamicin therapy may thus provide a readily available treatment for RDEB patients with nonsense mutations.
  • Difference types of keratinocyte gene therapy have been investigated in EB using either a retroviral vector or gene editing with CRISPR/Cas9. [1-3]
  • This latter technique has been shown to be efficient in a mouse model, and is thus a promising strategy.
  • HSV-1-based gene delivery targeting keratinocytes through topical delivery is also under study.
  • Another group has demonstrated that one or two subcutaneous injections of antisense oligoribonucleotides at doses ranging from 400 μg up to 1 mg restored type VII collagen expression and anchoring fibril formation in vivo in a xenograft model of recessive dystrophic epidermolysis bullosa skin equivalent. [4]
  • In a ground-breaking procedure, autologous transgenic keratinocyte cultures were demonstrated to have the capacity to regenerate an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of EB. [1]
  • The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection.
  • Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes.
  • While promising, successful gene therapy has been demonstrated in only a single case to date.
  • The case was well documented, but is not substitute for a clinical trial.
  • In addition, even if successful, the procedure is very expensive and would require extensive hospitalisation.
  • Regulatory issues are also likely to be complicated.
  • Successful gene therapy will require the development of safer vectors with a low risk of oncogenic potential.
  • Lastly, treatment should begin as early as possible.
  • While promising, successful gene therapy has been demonstrated in only a single case to date.
  • The case was well documented, but is not substitute for a clinical trial.
  • In addition, even if successful, the procedure is very expensive and would require extensive hospitalisation.
  • Regulatory issues are also likely to be complicated.
  • Successful gene therapy will require the development of safer vectors with a low risk of oncogenic potential.
  • Lastly, treatment should begin as early as possible.

Key messages/Clinical perspectives

  • Gene therapy of EB has the potential to restore functional correction of the disease, although these procedures are still experimental.


References

References


  1. Hirsch T, Rothoeft T, Teig N, et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature. 2017 Nov 16;551(7680):327-32.
  2. Bauer JW, Koller J, Murauer EM, et al. Closure of a large chronic wound through transplantation of gene-corrected epidermal stem cells. J Invest Dermatol. 2017 Mar;137(3):778-81.
  3. Takashima S, Shinkuma S, Fujita Y, et al. Efficient gene reframing therapy for recessive dystrophic epidermolysis bullosa with CRISPR/Cas9. J Invest Dermatol. 2019 Aug;139(8):1711-21.
  4. Turczynski S, Titeux M, Tonasso L, et al. Targeted exon skipping restores type vii collagen expression and anchoring fibril formation in an in vivo RDEB model. J Invest Dermatol. 2016 Dec;136(12):2387-95.

Presenter disclosure information: LK Bruckner-Tuderman: Constant Pharmaceuticals, FibrX, Lotus Tissue Repair, Shire.

Medical writer: Patrick Moore, PhD

Reviewer: Martina Lambertini, MD

Local reviewers: Martina Lambertini, MD (Italian); Alain Brassard, MD (French); Jorge Moreno González, MD (Spanish); Swen Malte John, MD, PhD (German); Marcelo Arnone, MD (Portuguese)

Scientific Editor: Prof. Brigitte Dréno, MD


CLINICAL TRIALS

PSORIASIS

Efficacy and safety of ixekizumab in a phase 3, randomized, double-blind, placebo-controlled study in paediatric patients with moderate-to-severe plaque psoriasis

Presented by: Prof. Kim A. Papp, Department of Medicine, Division of Dermatology, University of Toronto, Toronto, Canada

ATOPIC DERMATITIS

Efficacy and safety of baricitinib in combination with topical corticosteroids in moderate to severe atopic dermatitis: results of a phase 3 randomized, double-blind, placebo-controlled 16-week trial (BREEZE-AD7)

Presented by: Prof. Kristian Reich, Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, and Skinflammation® Center, Hamburg, Germany

PRURIGO NODULARIS

Phase 2b study of nemolizumab in patients with moderate to severe prurigo nodularis and associated severe pruritus

Presented by: Prof. Sonja Ständer, Department of Dermatology and Center for Chronic Pruritus (KCP), University Hospital Münster, Germany

VITILIGO

Efficacy and safety of a 52-week, randomized, double-blind trial of ruxolitinib cream for the treatment of vitiligo

Presented by: Dr. Amit G. Pandya, University of Texas Southwestern Medical Center, Dallas, TX, USA
 

EMERGING TERAPIES

PSORIASIS

Emerging therapies for psoriasis

Presented by: Prof. Michel Gilliet, Department of Dermatology, Lausanne CHUV, Switzerland

ATOPIC DERMATITIS

New and emerging therapies in atopic dermatitis

Presented by: Prof. Dagmar Simon, Department of Dermatology, Inselspital, Bern University Hospital, Bern, Switzerland

ONYCHOMYCOSIS

Emerging treatments for onychomycosis

Presented by: Dr. Ditte Marie L. Saunte, Department of Dermatology, Institute for Clinical Medicine, Zealand University Hospital, Roskilde, Denmark
 

REVIEW & UPDATES

ACNE & ROSACEA

Isotretinoin for acne and rosacea

Presented by: Dr. Pedro Mendes-Bastos, Dermatology Centre, Hospital CUF Descobertas, Lisbon, Portugal

ALOPECIA AREATA

New drugs for alopecia areata

Presented by: Prof. Spyridon Gkalpakiotis, Department of Dermatovenereology, Third Faculty of Medicine and University Hospital of Kralovske Vinohrady, Prague, Czech Republic.

DERMATOSURGERY

Update in dermatosurgery

Presented by: Prof. Eduardo Nagore, Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain

EPIDERMOLYSIS BULLOSA

New start of gene therapy in epidermolysis bullosa

Presented by: Prof. Leena K. Bruckner-Tuderman, University Medical Center, Albert-Ludwigs-University of Freiburg, Germany

MELANOMA

Treatment resistance in metastatic melanoma

Presented by: Prof. Martin Röcken, Department of Dermatology, Eberhard-Karls-University Tübingen, Germany

SCAR TREATMENT

Future of medical scar treatment

Presented by: Prof. Gabriella Fabbrocini, Department of Dermatology, University of Naples Federico II, Naples, Italy
 

EDUCATION FORUM

NON-MELANOMA SKIN CANCER

Systemic treatments of non-melanoma skin cancer

Presented by: Prof. Henrik F. Lorentzen, Department of Dermatology, Aarhus University Hospital, Denmark
 

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