
==== Front
Dermatol Ther (Heidelb)
Dermatol Ther (Heidelb)
Dermatology and Therapy
2193-8210
2190-9172
Springer Healthcare Cheshire

39112824
1239
10.1007/s13555-024-01239-4
Review
Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis
Koutsoukos Stefanos A. 12
Bilousova Ganna ganna.bilousova@cuanschutz.edu

12
1 https://ror.org/03wmf1y16 grid.430503.1 0000 0001 0703 675X Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 USA
2 https://ror.org/03wmf1y16 grid.430503.1 0000 0001 0703 675X Gates Institute, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 USA
7 8 2024
7 8 2024
9 2024
14 9 23792392
12 3 2024
12 7 2024
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2024
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Advancements in the molecular genetics of epidermolysis bullosa (EB) and ichthyosis, two rare inherited skin conditions, have enabled the identification of genetic variants that cause these diseases. Alongside technological advancements in genetic medicine, the identification of variants causal of these rare skin conditions has led to preclinical research and the clinical development of various in vivo and ex vivo gene and cell therapies for their treatment. Gene and cell therapies are considered to be the most advanced forms of personalized medicine, demonstrating safety and efficacy in numerous rare diseases. Although the orphan drug development boom has resulted in regulatory approval of multiple gene and cell therapies for various rare conditions, the application of these modalities to rare inherited skin conditions remains limited. Nonetheless, there are successful examples of both in vivo gene therapy- and ex vivo cell therapy-based approaches developed to treat EB and ichthyosis. This review highlights preclinical research and the clinical development of gene and cell therapies for multiple subtypes of these two devastating congenital skin conditions, including a gene therapy recently approved by the U.S. Food and Drug Administration for the treatment of recessive dystrophic EB.

Plain Language Summary

Advances in genetics research for skin diseases such as epidermolysis bullosa and ichthyosis have led to the discovery of many new subtypes of these severe skin conditions. Identifying new subtypes has in turn led to new treatments for these conditions, including gene and cell therapies. Gene and cell therapies aim to address the underlying genetic causes of disease and have already shown success in the clinic. While the development of such treatments for rare skin diseases has been limited, there are notable examples of gene and cell therapies developed for epidermolysis bullosa and ichthyosis. This review highlights recent developments in gene and cell therapy for epidermolysis bullosa and ichthyosis, including a newly approved gene therapy for recessive dystrophic epidermolysis bullosa.

Keywords

Cell therapy
Epidermolysis bullosa
Gene therapy
Ichthyosis
Rare disease
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pmcKey Summary Points

Advances in the molecular genetics of epidermolysis bullosa and ichthyosis, two rare inherited skin conditions, have allowed for the preclinical and clinical development of gene and cell therapies.	
Although regulatory agency incentives have broadly increased research, development, and market expenditures for rare diseases overall, rare dermatologic disorders have been relatively neglected.	
Gene and cell therapies for epidermolysis bullosa and ichthyosis are broadly modality agnostic and based on a variety of different technologies.	
The U.S. Food and Drug Administration approved the first gene therapy, Beremagene Geperpavec, for the treatment of recessive dystrophic epidermolysis bullosa in 2023.	
Gene therapy for the most common type of ichthyosis, lamellar ichthyosis caused by biallelic pathogenic variants in TGM1, is currently being developed using an engineered herpes simplex virus type 1 vector.	

Introduction

New insights into the molecular genetics of rare skin conditions such as epidermolysis bullosa (EB) and ichthyosis, along with technological advances in genetic medicine for rare monogenic diseases, have allowed for the research and development of gene and cell therapies for these devastating conditions.

Gene therapy, including both gene replacement and gene editing approaches, aims to either replace pathogenic alleles with their wildtype counterparts or permanently edit pathogenic variants in the endogenous genome. These gene therapy technologies have been evaluated in both preclinical and clinical settings, resulting in precise gene replacement or genetic correction for numerous rare inherited skin conditions. Cell therapy, which involves the use of gene therapies in combination with cell-based approaches, is another promising modality for the treatment of rare inherited skin conditions.

In this review, gene replacement and gene editing strategies delivered directly to an individual (by either viral or nonviral means) will be referred to as in vivo gene therapy, as illustrated in Fig. 1. Gene replacement and gene editing methods performed on cultured patient cells (such as dermal fibroblasts, keratinocytes, and induced pluripotent stem [iPS] cells), which are then transplanted to affected individuals, will be referred to as ex vivo cell therapy, as illustrated in Fig. 2. This review will highlight these therapeutic modalities as they relate to the treatment of various subtypes of both EB and ichthyosis.Fig. 1 In vivo gene therapy for epidermolysis bullosa and ichthyosis. In vivo gene therapy approaches for epidermolysis bullosa and ichthyosis, including gene replacement and gene editing, can be delivered by both viral and nonviral vectors. Beremagene Geperpavec (a gene therapy indicated for the treatment of wounds in patients with recessive dystrophic epidermolysis bullosa with mutations in the gene encoding the type VII collagen alpha-1(VII) chain [COL7A1]) and KB105 (an investigational gene therapy for lamellar ichthyosis caused by mutations in the transglutaminase 1 gene [TGM1]) both use a herpes simplex type 1 viral vector for the delivery of COL7A1 and TGM1, respectively. Illustration was created with BioRender.com

Fig. 2 Ex vivo cell therapy for the treatment of epidermolysis bullosa. Ex vivo cell therapy approaches, which have only been described for epidermolysis bullosa so far, require a primary specimen to be collected from a patient. These primary specimens are then genetically manipulated (sometimes alongside reprogramming) to either replace the pathogenic COL7A1 allele or correct the endogenous pathogenic variant using the CRISPR/Cas9 gene-editing technology. Corrected primary specimens can be transplanted directly onto the patient or grafted by epidermal sheets. Genetically corrected induced pluripotent stem cells can be differentiated into fibroblasts and keratinocytes and similarly, be grafted directly onto patients. Illustration was created with BioRender.com

Methods

A modality and stage of development agnostic literature review was performed by searching PubMed to identify relevant primary research relating to the research and development of therapies for epidermolysis bullosa, ichthyosis, and their subtypes.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Epidermolysis Bullosa and Its Subtypes

Epidermolysis bullosa is a group of rare inherited skin disorders characterized by skin fragility, blistering, and internal mucous membrane lesions. Twenty-one different genes have been implicated in EB of which most encode proteins localized to the dermal–epidermal junction [1].

Recessive Dystrophic Epidermolysis Bullosa

Genetics and Clinical Presentation

Often characterized as the most severe subtype of EB, recessive dystrophic EB (RDEB) (OMIM #226600) is caused by loss-of-function mutations in COL7A1, a gene encoding type VII collagen (collagen VII). Collagen VII is greatly reduced or absent in the fibroblasts and keratinocytes of individuals with RDEB, leading to the malformation or absence of anchoring fibrils and dermal–epidermal junction tissue separation. The disease causes skin fragility and predisposes affected individuals to severe blistering with minimal trauma, milia, atrophic scarring, dystrophic or absent nails, and alopecia. The mutational spectrum of RDEB spans all 118 exons of the COL7A1 gene but hotspot mutations have been reported that are associated with ethnicity [2].

Incidence and Prevalence

An analysis of the U.S. National Epidermolysis Bullosa Registry revealed the incidence and prevalence of RDEB to be 3.05 per one million live births and 1.35 per one million live births, respectively [3]. However, genotypic modeling of publicly available whole-exome and whole-genome data estimates an incidence of 95 cases per one million births. Chronic wounding and fibrosis associated with RDEB are believed to promote the development of aggressive cutaneous squamous cell carcinoma (cSCC), which is the leading cause of premature death in individuals with severe and intermediate RDEB [4, 5]. RDEB affects numerous organ systems, and extracutaneous manifestations of disease include anemia, growth retardation, dental caries, pseudosyndactyly, esophageal strictures, malnutrition, and ocular involvement [4]. Considering the severe manifestation of RDEB and significant reduction in quality of life of affected individuals, extensive research efforts have been undertaken to investigate novel treatments for RDEB. Highlights of these research and development efforts are described in the following text and summarized in Table 1.Table 1 Gene and cell therapies for recessive dystrophic epidermolysis bullosa in preclinical research and clinical development

Indication	Stage	Modality	Description	References	
RDEB	Approved (U.S. Food and Drug Administration)	Gene therapy	COL7A1 transgene delivered by an engineered HSV-1 vector	[10, 11]	
RDEB	Phase 3	Cell therapy	Genetically corrected autologous epidermal skin grafts	[7]	
RDEB	Preclinical	Cell therapy	CRISPR/Cas9 correction of COL7A1 in primary keratinocytes	[8]	
RDEB	Preclinical	Cell therapy	CRISPR/Cas9-based correction of COL7A1 in iPSCs and generation of organotypic induced skin composites	[12]	
RDEB	Preclinical	Cell therapy	CRISPR/Cas9-based correction of iPSCs and generation of human skin equivalents	[9]	
COL7A1 Gene encoding the type VII collagen alpha-1(VII) chain, CRISPR/Cas9 gene-editing technology, HSV-1 herpes simplex virus type 1, iPSCs induced pluripotent stem cells, RDEB recessive dystrophic epidermolysis bullosa

Preclinical and Clinical Studies

Genetically Corrected Autologous Epidermal Grafts

In 2016, Siprashvili et al. conducted a phase 1 clinical trial investigating the use of genetically corrected autologous epidermal grafts to treat RDEB [6]. Autologous keratinocytes from four patients with RDEB were transduced with a retrovirus encoding human COL7A1 and assembled into epidermal sheets, which were grafted onto six wounds per patient. All 24 grafts were well tolerated without serious adverse events. Collagen VII expression was observed in nine out of ten biopsies 3 months post-engraftment. Further, RDEB wounds treated with grafts displayed 87% healing at 3 months, 67% healing at 6 months, and 50% healing at 12 months compared to baseline wound sites [6].

A subsequent phase 1/2a clinical trial reported by Eichstadt et al. used the same methods on seven adults between 2013 and 2017, with follow-up for 2 to 5 years [7]. No serious adverse events occurred. At 6 months, wound healing of ≥ 50% was present in 95% of treated wounds and in 0% of untreated control wounds. After 1 year, 68% of treated wounds had ≥ 50% healing, compared to 17% of control wounds. After 2 years, 71% of treated wounds had ≥ 50% healing compared with 17% of control wounds.

Although this approach showed promise for wound healing in RDEB, the response was variable among patients, and grafted sites generally declined after 12 months in the single-center phase 1 clinical trial. In the study of Eichstadt et al. [7], collagen VII expression was reported to persist for up to 2 years in two participants. However, the use of retrovirus to generate collagen VII-corrected grafts could have safety limitations, as this approach can lead to undesired integrations of the viral genome throughout recipient cells. While this research provides a strong basis for developing cell-based approaches to treat RDEB, advanced methods of genetic correction would offer safer treatments and reduce unintended consequences of viral genome integration.

CRISPR/Cas9 Editing in Primary Patient-Derived Keratinocytes

In 2017, Hainzl et al. described a COL7A1 CRISPR/Cas9-based gene editing strategy in primary patient-derived keratinocytes [8]. CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) was used to correct a common insertion variant in exon 80 of COL7A1 (c.6527insC). Corrected keratinocyte clones were able to express and secrete collagen VII at levels similar to control keratinocytes. Transplantation of skin equivalents derived from the corrected keratinocytes onto an immunodeficient mouse rescued the disease phenotype with normal collagen VII localization at the basement membrane zone. In this study, the authors demonstrated the potential of CRISPR/Cas9 technology as a possible ex vivo treatment approach for genetic skin diseases.

CRISPR/Cas9 Editing in iPSCs and Generation of Human Skin Equivalents

In 2019, Jackow et al. reported a CRISPR/Cas9-based editing approach of COL7A1 for the correction of RDEB causing variants in iPS cells [9]. The authors demonstrated the successful correction of two pathogenic variants in exon 19 and exon 32 of the COL7A1 gene by homology-directed repair in iPS cells derived from patients with RDEB. Human skin equivalents were generated from genetically corrected iPS cells and grafted onto immunodeficient mice. Grafts showed normal expression of collagen VII at the basement membrane zone and the restoration of anchoring fibrils two months post grafting. Safety assessment of Cas9 cleavage activity did not reveal any unintended nuclease activity.

Transgenic COL7A1 Delivery by an Engineered human Herpes Simplex Virus Type 1 Vector

In 2022, an engineered, non-integrating, replication-incompetent human herpes simplex virus type 1 (HSV-1) vector formulated in a gel was reported to be both safe and effective in the healing of wounds in individuals living with RDEB. In a randomized, placebo-controlled, phase 1 and 2 clinical trial (ClinicalTrials.gov identifier: NCT03536143), sponsored by Krystal Biotech, Inc. (Pittsburgh, PA, USA), the safety and efficacy of this therapeutic, known as Beremagene Geperpavec (B-VEC), was evaluated in nine individuals with RDEB across 28 wounds [10]. The primary outcome measures of the study were met. Notably, ten out of 12 wounds (83%) closed in individuals receiving B-VEC compared to one out of seven (14%) in individuals receiving placebo after 12 weeks, a difference of 69%. The median time to complete closure was 13.5 days in individuals treated with B-VEC and 22.5 days in those receiving placebo. The median duration of closure was 103.0 days in the B-VEC-treated group and 16.5 days in the placebo group. This phase 1 and 2 study showed that B-VEC is a safe and effective therapy in the promotion of wound healing in individuals living with RDEB.

B-VEC was further evaluated in a phase 3, double-blind, intrapatient randomized, placebo-controlled trial that included affected individuals aged ≥ 6 months [11]. A primary wound pair was selected for each patient and matched according to size, region, and appearance. Each wound was assigned to either the group receiving weekly application of B-VEC or the group receiving placebo. Complete wound healing was observed in 67% of wounds treated with B-VEC compared to 22% of wounds exposed to placebo across 31 patients. Complete wound healing at 3 months was observed in 71% of wounds treated with B-VEC compared to 20% of wounds exposed to placebo. Adverse events experienced by individuals receiving B-VEC included pruritus and chills. In May of 2023, B-VEC was approved by the U.S. Food and Drug Administration. This was the first topical gene therapy approved for the treatment of wounds in patients with RDEB.

GMP Compatible CRISPR/Cas9-Based Editing of iPSCs and Generation of Induced Skin Composites

In 2024, Neumayer et al. reported a scalable, Good Manufacturing Practice (GMP) compatible, autologous cell therapy for RDEB [12] that was able to generate clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts for the treatment of wounds in patients with collagen VII deficiency. The approach involved a combined reprogramming and CRISPR-based genetic correction to generate COL7A1-corrected clonal iPS cells from primary patient fibroblasts and, further, iSC grafts using a novel two-dimensional organoid differentiation protocol. The authors reported that iPS cell-derived iSC generation was reproducible using cells from four patients with RDEB with different pathogenic variants, and the grafts were able to develop into stable stratified skin with functional collagen VII restoration in immune-compromised mice.

Both the Jackow et al. [9] and Neumayer et al. [12] studies report, for the first time, the generation of an iPS cell- and CRISPR/Cas9-based cell therapy for the treatment of RDEB. Although still early in the preclinical stages, these methods represent safer and potentially more durable alternatives compared to previous studies using viral approaches for transgenic COL7A1 delivery.

Epidermolysis Bullosa Simplex

Genetics and Clinical Presentation

Epidermolysis bullosa simplex (EBS) (OMIM #131760) is a rare inherited skin blistering condition caused by monoallelic pathogenic variants in KRT5 and KRT14, genes which encode keratin 5 and keratin 14, respectively, that are localized to the epidermal basal layer [13]. Pathogenic variants in both KRT5 and KRT14 have been shown to disrupt the central alpha helical segment of these molecules and further compromise the structure and function of the cell cytoskeleton and its ability to accommodate mechanical stress [14]. Structural deficits in the cytoskeleton caused by KRT5 and KRT14 pathogenic variants predispose the basal cell layer to fracture. Ultrastructural assessment of keratin 5 and keratin 14 abnormalities reveals cell vacuolization, keratin filament aggregation, and blister formation [15].

Clinically, all forms of EBS manifest with skin blistering that is usually induced by mechanical friction or trauma exposure. Additional manifestations include palmoplantar keratoderma (thickening of the palmar and plantar skin), nail dystrophy and shedding, alopecia, and mucosal tissue involvement (rare observation usually exclusive to more severe cases). Erosions and blistering heal without scarring but result in hyperpigmentation.

The age of onset in EBS is variable, but most severe cases present at birth and less severe cases during the second or third decade of life [16]. Improvement with age is common.

EBS is typically inherited in an autosomal dominant manner, but 30% of cases in the Middle East are caused by recessive variants [17, 18]. Most pathogenic variants causal in EBS induce a dominant negative effect by which mutant molecules interfere with the wildtype molecules. This interaction has major implications for the development of therapies for EBS.

Preclinical and Clinical Studies

In 2017, Kocher et al. reported an efficient homology-directed repair of dominant negative KRT14 variants with CRISPR/Cas9 nickase [19]. A hotspot mutation in exon six of the KRT14 gene, which causes generalized severe EBS, was corrected using a double-nicking strategy targeted against exon 7 and followed by homology-directed repair. The use of Cas9 nickase (D10A), a single guide RNA, and minicircle donor vector with the donor template resulted in a recombination efficiency of > 30% and correction of the negative KRT14 allele. Immunofluorescence analysis showed phenotypic correction by the absence of keratin 14 aggregates within the cytoplasm. The safety profile of this double nicking strategy was found to be promising, with no detectable off-target activity in a set of predicted off-target genes confirmed by next-generation sequencing.

Junctional Epidermolysis Bullosa

Genetics and Clinical Presentation

Junctional epidermolysis bullosa (JEB) (OMIM #226650) is a rare inherited skin blistering disorder caused by biallelic pathogenic variants in the LAMA3, LAMB3, and LAMC2 genes and is characterized by skin and mucous membranes. LAMA3, LAMB3, and LAMC2 proteins, together, assemble into the laminin 332 heterotrimer, also referred to as LAM5 [20]. Pathogenic variants in the LAM5 subunits affect the ability of these polypeptides to assemble into a trimeric molecule, compromising their secondary structure and, further, their ability to form intracellular anchoring fibrils in the lamina densa.

JEB is classified into two subtypes: generalized and localized. JEB generalized severe is the result of little or no functional protein [21]. Disease severity is associated with premature termination of the protein [22]. JEB generalized intermediate results from single amino acid substitutions and splice-junction variants. JEB presents with blistering, which can be severe but typically heals with minimal scarring [23, 24].

Pathogenic variants in COL17A1, the gene encoding type XVII collagen (collagen XVII), have also been determined to be causal in JEB, specifically the generalized intermediate subtype [25]. Collagen XVII is a key component of hemidesmosomes, which anchor basal keratinocytes to the underlying basement membrane. Collagen XVII deficiency causes skin fragility, dental manifestations, and alopecia, all of which are characteristic symptoms of JEB generalized intermediate.

Preclinical and Clinical Studies

In 2006, the first ex vivo gene replacement and cell transplantation approach for JEB was reported [26]. Epidermal stem cells were isolated from an adult with LAM5-β3-deficient JEB and transduced with a retroviral vector expressing LAMB3 complementary DNA (cDNA). Genetically corrected keratinocytes were used to generate epidermal grafts. Upon transplantation back to the patient, the grafts showed restored LAM5-β3 expression and proper assembly of functional LAM5, resulting in a durable, adherent epidermis throughout the 1-year follow-up period. This study demonstrated a successful ex vivo gene replacement and transplantation strategy that resulted in a fully functional epidermis and amelioration of the disease.

In 2017, Bauer et al. published another gene replacement and transplantation approach [27]. A 49-year-old woman with generalized intermediate, laminin-322-B3-deficient JEB presented with a large 80-cm2 wound on her leg. Primary keratinocytes were transduced with a retroviral vector expressing full-length LAMB3 cDNA, as used in the previously described study. Epidermal sheets generated with corrected keratinocytes were grafted onto the leg ulceration, resulting in wound closure with no blister formation throughout the 16-month follow-up period.

In the same year, a similar approach regenerated the entire human epidermis in a 7-year-old with JEB [28]. About 80% of the individual’s total body surface area was replaced with transgenic epidermal grafts generated from genetically corrected autologous keratinocytes. Clonal tracing revealed that a limited number of long-lived stem cells could sustain the fully regenerated human epidermis, confirming the feasibility of ex vivo gene and cell therapy approaches to replace defective skin with corrected skin.

In 2018, Benati et al. used CRISPR/Cas9 was used to correct LAMB3 variants in keratinocytes derived from an individual with JEB [29]. CRISPR/Cas9 was used to restore LAMB3 expression in vitro, followed by transplantation onto immunodeficient mice. The grafting of genetically corrected skin equivalents onto immunodeficient mice demonstrated a complete rescue of dermal–epidermal junction integrity.

Ichthyosis and Its Subtypes

Inherited ichthyotic conditions are genetic disorders commonly characterized by general dry skin, scaling, hyperkeratosis, and erythroderma [30]. Recent advances in human genetics and next-generation sequencing have enabled the identification of numerous genes causal in their pathogenesis [31]. Ichthyotic conditions are classified as either syndromic or non-syndromic [32]. Non-syndromic ichthyosis presents exclusively in the skin, while syndromic subtypes involve multiple body systems.

Due to their rare and ultrarare incidence, gene therapy for the ichthyoses is rarely investigated. However, gene therapy for ichthyosis is a promising therapeutic approach due to the monogenic nature and tissue accessibility associated with this condition. Here we review in vivo gene therapies for nonsyndromic ichthyosis (specifically autosomal recessive congenital ichthyosis) in both the preclinical and clinical settings.

Autosomal Recessive Congenital Ichthyosis

Autosomal recessive congenital ichthyosis (ARCI) is a genetically and phenotypically heterogenous group of disorders that includes harlequin ichthyosis (HI), lamellar ichthyosis (LI), and congenital ichthyosiform erythroderma [33]. ARCI is caused by pathogenic variants in multiple genes, including TGM1 [34], ABCA12 [35, 36], CYP4F22 [37, 38], ALOXE3/ALOX12B [39, 40], NIPAL4 [41, 42], CERS3 [43, 44], SDR9C7 [45–48], PNPLA1 [49–56], SLC27A4 [57–66], and LIPN [67]. Overall, ARCI has an incidence of about 1 per 100,000 general population, and 24–34% of cases are caused by pathogenic variants exclusively in TGM1 [33, 68].

Lamellar Ichthyosis

Genetics and Clinical Presentation

About 70–90% of cases of LI (OMIM #242300) have pathogenic variants in the gene encoding transglutaminase 1 (TGM1). LI typically presents at birth with a collodion membrane, which is replaced by large, brown, plate-like scales in a generalized distribution. Erythroderma may be present but is usually mild. Scaling leads to sweat duct obstruction and severe heat intolerance. As LI is one of the most common subtypes of ichthyosis, a multitude of gene and cell therapies for its treatment have been investigated in both preclinical and clinical settings.

Preclinical and Clinical Studies

In 1996, Choate et al. described one of the first experimental gene therapies for LI caused by transglutaminase 1 (TGM1) deficiency [69]. The authors showed that TGM1 expression could be restored in primary patient keratinocytes using a retroviral vector. These retrovirally-corrected keratinocytes also demonstrated restored involucrin cross-linking and normal in vitro measures of cornification.

In 2021, Freedman et al. described a modified herpes simplex virus type 1 vector (KB105) encoding human TGM1 for the treatment of ARCI [70]. KB105 efficiently transduced TGM1-deficient human keratinocytes, promoted TGM1 expression, and rescued enzymatic deficiency. In vivo topical application restored protein expression in the epidermal layer without inducing fibrosis, necrosis, or acute inflammation. KB105 is currently being investigated in a phase ½ clinical trial (ClinicalTrials.gov identifier: NCT04047732).

In 2021, Dang et al. reported the correction of pathogenic variants in TGM1 by adenine base editing in human embryos [71]. Two different adenine base editors in combination with truncated single guide RNAs (sgRNAs) were used to repair the pathogenic variant in mutant zygotes, providing feasibility data for developing in utero gene correction approaches for ichthyosis.

Harlequin Ichthyosis

Genetics and Clinical Presentation

Harlequin ichthyosis (OMIM #242500) is widely considered to be the most severe subtype of ichthyosis. The clinical presentation of HI includes thick, plate-like scales with severe ectropion, eclabium, and flattening of the ears [72]. The development of the skin in utero is characterized by hyperkeratosis of the hair canals and ultrastructural abnormalities, including abnormal lamellar granules in the fetal epidermis [73, 74]. In 2005, two sets of authors (Akiyama et al. [36] and Kelsell et al. [35]) reported that HI is caused by loss-of-function mutations in the gene ABCA12, which encodes the adenosine triphosphate (ATP)-binding cassette family subfamily A member 12. Loss-of-of-function variants in ABCA12 disrupt normal lipid transport in lamellar granules, particularly in keratinocytes undergoing keratinization in the epidermis [36].

Translational efforts in the development of gene therapy for HI have been extensive due to its devastating clinical presentation. In 2005, Akiyama et al., in addition to characterizing its genetic etiology, also showed the rescue of lamellar granules lipid secretion through corrective gene transfer of ABCA12 by transfection of a plasmid containing full-length cDNA [36].

Conclusion

Overall, the research and development of gene and cell therapies for the treatment of EB and ichthyosis are in their infancy and are primarily focused on more prevalent subtypes. Recent advancements in the clinical development of products indicated for the treatment of these conditions provide a promising foundation for future research and development. However, the low incidence and prevalence of these indications continue to pose challenges in securing funding in both academic and industrial settings. In order to improve the outcomes of individuals living with rare inherited skin conditions, innovative approaches in platform technology development, alongside regulatory acceptance of these platforms, will be required to ensure that these rare and ultrarare indications are not overlooked.

Author Contributions

All authors contributed to the study conception and design. The literature search was performed by Stefanos A. Koutsoukos and Ganna Bilousova. The first draft of the manuscript was written by Stefanos A. Koutsoukos, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

We are grateful for funding support from the National Institutes of Health (T32AR007411), Dystrophic Epidermolysis Bullosa Research Association (DEBRA) Austria, Gates Grubstake Fund, and the Gates Frontiers Fund. No funding or sponsorship was received for the publication of this article.

Declarations

Conflict of Interest

Stefanos A. Koutsoukos and Ganna Bilousova declare that they have no competing interest.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
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