Innovative Therapeutic Approaches for the Treatment of the Ocular Morbidities in Patients with EEC Syndrome

Cells. 2023 Feb 2;12(3):495. doi: 10.3390/cells12030495.

Abstract

Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) syndrome is caused by heterozygous missense point mutations in the p63 gene, an important transcription factor during embryogenesis and for stem cell differentiation in stratified epithelia. Most of the cases are sporadic, related to de novo mutations arising during early-stage development. Familial cases show an autosomic dominant inheritance. The major cause of visual morbidity is limbal stem cell failure, which develops in the second to third decade of life. Patients often show ocular surface alterations, such as recurrent blepharitis and conjunctivitis, superficial microlesions of the cornea, and spontaneous corneal perforation and ulceration, leading to progressive corneal clouding and eventually visual loss. No definitive cures are currently available, and treatments to alleviate symptoms are only palliative. In this review, we will discuss the proposed therapeutic strategies that have been tested or are under development for the management of the ocular defects in patients affected by EEC syndrome: (i) gene therapy-based approaches by means of Allele-Specific (AS) siRNAs to correct the p63 mutations; (ii) cell therapy-based approaches to replenish the pool of limbal stem cells; and (iii) drug therapy to correct/bypass the genetic defect. However, as the number of patients with EEC syndrome is too limited, further studies are still necessary to prove the effectiveness (and safety) of these innovative therapeutic approaches to counteract the premature differentiation of limbal stem cells.

Keywords: EEC syndrome; cornea; epithelial stem cells; induced pluripotent stem cells (IPSCs); p63; siRNA.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cleft Lip* / genetics
  • Cleft Lip* / therapy
  • Cleft Palate* / genetics
  • Ectodermal Dysplasia* / diagnosis
  • Ectodermal Dysplasia* / genetics
  • Ectodermal Dysplasia* / therapy
  • Humans
  • Transcription Factors / metabolism

Substances

  • Transcription Factors

Supplementary concepts

  • Ectrodactyly-cleft lip-palate syndrome

Grants and funding

This work was supported through grants from the Italian Ministry of Health RF-2016-02361159: “Advanced therapy medicinal products for the treatment of ocular defects in Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) syndrome”, CUP n. I74I18000160006 to Enzo Di Iorio.