Over-activation of the involved pathway may be caused by a gain of function (GOF) of a main protein or, alternatively, by loss of function (LOF) of an inhibiting protein. To illustrate, Costello syndrome is caused by GOF mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS) gene, whereas neurofibromatosis Type 1 is due to LOF mutations in NF1 gene (Walker and Upadhyaya, 2018). Both genetic variants result in an overactive mitogen-activated protein kinase (MAPK) pathway, commonly called RASopathies. Inhibiting this overactive pathway is thus a logical option, with similar drugs possibly used for different RASopathies. However, the overactive RAS proteins resulting from LOF variants in NF1 might activate several downstream pathways. This may be tissue-dependent, as hypothesised in NF-1; as a result, this requires targeting different manifestations, separately. Hence, the optimal treatment for neurofibromas may be different from those involving skeletal abnormalities or cognitive dysfunction (Walker and Upadhyaya, 2018). Fortunately, for many pathways, drugs have already been developed in the framework of other pathologies. Commonly, these are often anti-cancer drugs that may be repurposed for use in genodermatoses, provided that undesirable effects are acceptable.

A recent example is the orphan genodermatosis Olmsted syndrome. It is a rare form of painful mutilating palmoplantar keratoderma (PPK), presenting early in life with periorificial keratotic plaques, which are at times associated with alopecia, along with a risk to develop spinocellular carcinomas later in life. The cause in most patients is a heterozygous GOF mutation in transient receptor potential vanniloid-3 (TRPV3), which encodes Ca²⁺ permeable channels. The latter form a signalling complex with transforming growth factor-α (TGF-α) and epidermal growth factor receptor (EGFR). Over-activation of the channels stimulates TGF-α release, which in turn is a stimulating ligand for EGFR. This results in an increased channel activity, hence creating a positive feed-back loop. In a proof of concept study, three patients with activating TRPV3 mutations were treated using erlotinib, an EGFR-blocker (Greco et al., 2020). Within 3 months after initiating therapy, PPK had drastically improved and pain disappeared.

Another illustration is Gorlin syndrome, also referred to as nevoid basal cell carcinoma (BCC) syndrome, which is caused by LOF variants in the tumour suppressor patched-1 homolog gene (PTCH1), provoking release of smoothened (SMO) oncogene inhibition. This results in the subsequent re-activation of the Hedgehog-signalling pathway. Vismodegib, which is a SMO inhibitor, was able to reduce not only the tumour burden and induction of new BCC, but also the growth of jaw keratocystic odontogenic tumours in Gorlin patients (Booms et al., 2015).

Intervening within a pathway that is less active or even inactive appears to be more challenging. DNA-repair disorders are caused by a defective DNA-repair pathway that was initially aimed at restoring genomic damage. As a result, naturally occurring DNA lesions are rapidly neutralized. If this pathway is defective, this predisposes to cancer. Only very few therapeutic possibilities are available for these diseases (de Andrade et al., 2021) (Weon and Glass, 2019). Screening of a library comprising Food and Drug Administration (FDA)-approved drugs has shown that the sulfonylureas acetohexamide and glimepiride are able in vitro to enhance viability in XPA cells after UV radiation at rather high dosages (Mazouzi et al., 2017). The exact mechanism is not yet understood. Moreover, preliminary data suggest that nicotinamide or other SIRT-1 inhibitors could be of benefit for XPD/CS patients by decreasing not only UV damage but also preventing neurological degradation. Nevertheless, further studies are needed to confirm these encouraging results (Vélez-Cruz et al., 2013).

Erythropoietic protoporphyria is most often caused by a biallelic loss of function mutation in the gene encoding ferrochelatase, thereby abolishing normal haem production and resulting in the accumulation of protoporphyrin in erythroid cells. The accumulated phototoxic protoporphyrin in superficial vessels is activated by blue light. From early childhood on, severe neuropathic pain, followed by oedema and blistering develops within minutes after sun exposure, which obliges patients to avoid any sun exposure. A recent therapeutic approach is the stimulation of photoprotective eumelanin production by stimulating the melanocortin 1 receptor in melanocytes using its agonist afamelanotide. The latter is a potent analogue of human α-melanocyte-stimulating hormone. Clinically, this approach has been shown to enable symptom-free sun exposure, thereby improving patients quality of life (Langendonk et al., 2015).

The genetic defects underlying genodermatoses likely induce an inflammatory reaction cascade, which contributes to the phenotypic presentation.

The hereditary ichthyoses are a large group of various diseases presenting with hyperkeratosis, scaling, and mostly different degrees of inflammation that involves the entire skin. These conditions are manifest from birth on; in rare cases, they are associated with other organ involvements (Mazereeuw-Hautier et al., 2019). This entity is a diverse group, with more than 50 genes so far identified as the underlying cause. Phenotypically, these conditions present as ichthyosis vulgaris, recessive X-linked, epidermolytic, autosomal recessive congenital ichthyosis (ARCI), and NS, among others. To date, treatment is largely focussed on targeting hyperkeratosis with topical agents and retinoids (Mazereeuw-Hautier et al., 2019). Besides, anti-inflammatory treatments based on corticosteroids and calcineurin inhibitors are commonly employed so as to control inflammation (Mazereeuw-Hautier et al., 2019). More recently, biotherapies targeting the inflammatory process, including TNF-α inhibitors and omalizumab, have been used with some success (Fontao et al., 2011; Yalcin, 2016; Roda et al., 2017).

Surprisingly, a study evaluating the immune dysregulation in patients suffering from ichthyosis identified a large number of ichthyosis subtypes that share IL-23/Th17 skewing in the skin (Paller et al., 2017). This observation offered a more solid pathophysiological basis for new treatment targets. Ustekinumab is a human monoclonal antibody that binds to the p40 subunit common to both Il-12 and Il-23. This agent thus blocks the binding of these cytokines to their receptor, and it has been successfully applied in a patient suffering from erythrodermic ichthyosis caused by a biallelic pathogenic variant in NIPAL4 (Poulton et al., 2019). This agent has also been employed with success in a patient with NS (Volc et al., 2020), and in another patient exhibiting a biallelic mutation in desmoplakin that manifested as ichthyosis (Paller et al., 2018). Different case reports and small series have already been published focussing on Il-17 inhibitors such as sekukinumab (Blanchard and Prose, 2020; Luchsinger et al., 2020; Barbieux et al., 2021) in NS, although sustained improvement could not be obtained in one patient. Given that, after this treatment, a Th2 signature remained (Barbieux et al., 2021), using dupilumab, a blocker of the IL-4 receptor’s alpha-chain, thereby blocking Il-4 and Il-13 cytokines, could be another target for some NS patients, as it has already been tested with encouraging results (Andreasen et al., 2020; Steuer and Cohen, 2020; Süßmuth et al., 2021).

A recent paper identified potential therapeutic targets for Harlequin ichthyosis (HI), which is the most severe form of ichthyosis, and it is often associated with marked neonatal lethality. In an in vitro model, investigators discovered an upregulation of IL-36α and IL-36γ, as well as of STAT1 and its downstream target, consisting of inducible nitric oxide synthase (NOS2). Treatment using either a NOS2-inhibitor or the JAK inhibitor tofacitinib was proven able to restore the lipid barrier in the HI 3D-model (Enjalbert et al., 2020). Drugs blocking either Il-36 or downstream IL-23 and IL-17 would probably be an option that deserves to be considered. Il-36 cytokines are secreted by keratinocytes, representing a danger signal. Hence, we believe this cytokine to be a potential candidate, given that it is one of the earliest cytokines that are being secreted in response to barrier disruption, as seen in ichthyosis.

However, more large-scale studies are now needed, seeking to evaluate the effect of these different biologicals and identify the precise patient profile that would best respond to the different drugs. So far, several trials have already been initiated (see Table 1).

Pustular psoriasis, due to a LOF mutation of Il36RN that encodes a receptor antagonist, is another disease candidate for IL-36 antagonists (Gooderham et al., 2019). Interestingly, improvement after one single injection was already observed in a proof-of-concept study involving spesolimab. This compound, which is an Il-36R blocker is investigated in a recent study (NCT02978690), however was, associated with mild to moderate undesirable effects, including infections, fever, or arthralgia, in all the seven patients that were tested. It will certainly be interesting to further assess this compound’s clinical effects and undesirable effects, as well (Bachelez et al., 2019), in larger-scale clinical trials (Choon et al., 2021), (Table1).

Familial pityriasis rubra pilaris (PRP) is commonly caused by heterozygous GOF mutations of CARD14 (Fuchs-Telem et al., 2012), which is a regulator of nuclear factor-κB (NF-κB-) signalling. As this pathway positively regulates Th17 differentiation, and in turn is regulated by TNF-α, indeed treatment with TNF-α inhibitors (Vasher et al., 2010), Th-17 inhibitors (De Felice et al., 2020) and IL12/IL23 inhibitors have been effective treatments (Eytan et al., 2014; Lwin et al., 2018). As the same CARD14 mutations have been associated with familial early-onset psoriasis (Craiglow et al., 2018), ustekinumab, namely an Il12/Il23-antagonist, may prove to be effective in these psoriasis patients (Signa et al., 2019).

However, other genodermatoses could also be candidates for targeting inflammatory mediators, provided that inflammation is actually part of their clinical manifestations. To illustrate, severe generalised EB simplex is a genodermatosis that manifests as skin blistering upon minimal trauma. This condition is caused by heterozygous KRT14 mutations, the pro-inflammatory cytokine Il-1 being strongly expressed. Diacerein is a down-regulator of the Il-1 signalling cascade, which is administered in a cream formulation. This agent has proven to be effective in reducing the number of blisters, without significant undesirable effects (Wally et al., 2018; Limmer et al., 2019). Diacerein is also under investigation for EB which is caused by mutations in other genes. AC-203 is another drug with similar properties, which is currently under investigation (Table 1). Targeting Th-17 cells, as well as TGF-β or Th-2 cytokines represent other therapeutic options (Nyström et al., 2015; Castela et al., 2019; Shehadeh et al., 2020; Zhou et al., 2021).

Table 1 provides a summary of genodermatoses, while also listing the new or repurposed drugs currently under investigation.

Nonsense mutations leading to premature termination codons (PTCs) and truncated inactive or decoyed proteins are estimated to be the cause of about 11% of all monogenic diseases. Repurposed drugs like aminoglycosides favour, during translation, mispairing of near-cognate tRNA at the place of the premature termination, resulting in the incorporation of a different amino-acid into the translated protein. Usually, this transforms a nonsense mutation into a missense mutation, thereby restoring the full-length protein (Figure 1) (Nagel-Wolfrum et al., 2016).

In genodermatoses, topical gentamycin administration on skin lesions in Hailey-Hailey disease (HHD) (Kellermayer et al., 2006), hereditary hypotrichosis simplex (Peled et al., 2020), and PPK caused by SERPINB7 mutations (Ohguchi et al., 2018), as well as topical or intradermal (ID) gentamycin administration in dystrophic EB (Woodley et al., 2017) have already been tested, yet with variable results. Moreover, in vitro tests in JEB cells were demonstrated to restore expression of laminin 332, (Lincoln et al., 2018), and of XPC in XP cells (Kuschal et al., 2015).

More studies are presently ongoing including topical application GENTELBULL (NCT04644627), with topical BPM 31510 cream (NCT02793960) in EB; intravenous (IV) administration in both JEB (NCT03526159) and DEB (NCT03392909). Trial NCT03012191 in DEB has been completed, with preliminary results showing some C7 expression in exclusively the skin in IV- or ID-treated patients, yet not in topically-treated patients.

Although these readthrough drugs look promising and could be applied in numerous genetic diseases, currently available compounds exhibit weak (less than 5%) activity in vitro, and in only a fraction of tested patients. Moreover, the oto- and nephrotoxicity of aminoglycosides is a concern in the event of long-term administration, as is the risk of antibiotic resistance if these drugs are topically applied on chronic wounds, such as in EB. There is an ongoing search for new compounds with a good safety profile or for drug combinations [for a review see (Baradaran-Heravi et al., 2016; Nagel-Wolfrum et al., 2016)]. A recent study investigated amlexanox, which has proven to be effective in cultured fibroblasts and keratinocytes from dystrophic EB patients (Atanasova et al., 2017).

Replacement of the protein encoded by the mutated gene is currently under investigation in different genodermatoses (Figure 2A). A proof of concept study using a mice model for dystrophic EB, based on missing Type VII collagen (C7) anchoring fibrils, has demonstrated that injecting normal C7 is indeed able to form anchoring fibrils at the dermo-epidermal junction (DEJ). This ability was demonstrated not only in the skin but also in the oesophagus, lasting for several weeks and preventing the mice from dying (Woodley et al., 2013; Hou et al., 2015).

Presently, phase 1 and 2 studies in humans are ongoing, administering IV recombinant C7 in recessive DEB (PTR-01) (NCT03752905 and NCT04599881). Immunogenicity does not appear to be a big issue. However, their size and tendency to form aggregates likely limit skin and other tissue homing. The drug has orphan designation.

Similar ongoing studies are focused on transglutaminase-1 (TGM-1)-deficient ARCI. In a skin humanized mouse model, topical application of liposomes containing recombinant human TG1 (rh-TG1) resulted in considerable improvement in ichthyosis phenotype, as well as normalization of the regenerated ARCI skin (Aufenvenne et al., 2013). More recently, such positive outcome was confirmed in a skin equivalent model using thermo-responsive nanogels (tNG) encapsulating TG1 (Witting et al., 2015; Plank et al., 2019).

The timing of protein replacement appears essential, as illustrated in hypohidrotic ectodermal dysplasia (HED), which is a disease that affects several ectodermal structures. Sweat glands, teeth development, and meibomian glands are severely impaired in this condition, with distinctive facial features usually present, as well as sparse blond hair. The condition’s most common cause is a recessive X-linked mutation in ectodysplasin A (EDA) (Schneider et al., 2018). The inability to sweat may be life-threatening due to hyperthermia.

Fc-EDA, which is a fusion protein linking the constant domain of IgG1 and the receptor-binding portion of EDA, was administered prenatally via amniocentesis into the amniotic cavities of three foetuses of two different pregnancies, namely at Week 26 for one and for the twins at Week 26 and Week 31. Sweat glands, meibomian glands, and tooth germs almost normally developed in the new-borns, being more numerous than in their affected older brothers (Schneider et al., 2018). However, when this Fc-EDA was administered to a baby at birth, no effect was observed, which further underlines that administration must be performed when the pathway is active, meaning between Weeks 20–30 during foetal development for sweat glands. Nevertheless, a larger study with EDI200 administered immediately after birth has been completed, while still awaiting results (NCT01775462).

For genetic diseases caused by retention of the defective protein within the endoplasmatic reticulum, due to misfolding and subsequent absence of transport to the Golgi apparatus, chaperone therapy is under investigation, mostly based on low concentrations of competitive inhibitors. By binding to misfolded enzymes and forming stable complexes instead, the transport and further processing into the Golgi apparatus is being restored. As a result, some (variable) enzymatic activity and partial phenotype rescue is rendered possible (Figure 2B). This technique is under investigation for storage diseases like Gaucher and Fabry disease and also in oculo-cutaneous albinism Type A (OCA1A), (Table 2) (Lenders and Brand, 2021; Teramae et al., 2019), while it may also be taken into consideration for keratinopathies (Chamcheu et al., 2011).

Both enzyme replacement and chaperone therapy are similarly being investigated for the treatment of porphyrias. Nevertheless, the major drawback of these approaches consists in their delivery to the targeted organ (Bustad et al., 2021).

Restoring the defective protein by administrating allogeneic cells is another approach in managing genodermatoses (Figure 3). Collagen 7 (C7) is produced by keratinocytes and fibroblasts. Early experiments showed that IV injection of human fibroblasts in athymic mice resulted in the deposition of human C7 that formed anchoring fibrils at the DEJ, yet which occurred in wounded but not in normal mice skin (Woodley et al., 2007). Subsequently, three studies conducted in humans demonstrated ID injection of allogeneic fibroblasts to fasten the healing of wounds in most tested DEB patients (Petrof et al., 2013; Venugopal et al., 2013; Moravvej et al., 2018). Nevertheless, no difference in healing time was observed in comparison with the lesions injected with the vehicle containing albumin and growth factors (Venugopal et al., 2013). Interestingly, the patients who failed in these three studies were unable to express own C7, while the anchoring fibrils seen in the biopsies were rudimentary (Wong et al., 2008). Despite the allogeneic fibroblasts disappearing after 2 weeks, the clinical effect of one single injection lasted 1 month in one study (Petrof et al., 2013), and up to 3 months in another (Moravvej et al., 2018), with C7 expression sustained over 9 months. In contrast with the animal studies, this clearly suggests that the major effect probably consisted of an increase in recipients COL7A1 mRNA and mutant C7 levels, which was induced by paracrine mediators secreted by the allogeneic fibroblasts (Wong et al., 2008), such as heparin-binding epidermal growth factor-like growth factor (HB-EGF) (Nagy et al., 2011).

Allogeneic bone marrow (BM) transplantation is a technique that was primarily designed to treat hematopoietic malignancies. Later on, this technique was found to be effective in reversing the phenotype of some genetic diseases, primarily comprising primary immune-deficiencies. However, this same approach has also been shown to attenuate the muco-cutaneous manifestations and improve the quality of life of severe JEB and DEB (Wagner et al., 2010). By reducing the intensity of the conditioning regimen, essential undesirable effects and mortality could be reduced (Tolar and Wagner, 2013). Further research allowed for unravelling the potential underlying mechanism (Tamai and Uitto, 2016), thereby refining the technique. Release of high mobility group box 1 protein (HMGB1) from necrotic epithelial cells does transfer signals to bone marrow-derived PDGFRa⁺/CXCR4⁺ cells. This leads to their migration into circulation, along with subsequent homing to the damaged skin through stromal cell-derived factor 1a (SDF-1a)/CXCR4 axis (Tamai and Uitto, 2016). The most essential action of MSCs is likely the secretion of anti-inflammatory agents, whereas they may also differentiate into fibroblasts and keratinocytes. Transplanted patients are able to receive skin grafts from the same donor, which survive for long periods and outgrow into adjacent wounds, thereby suggesting immune tolerance and outgrowth of stem cells (Ebens et al., 2020).

Three open clinical trials have been conducted to date, involving subjects with RDEB using MSCs from healthy donors. Of these, two were carried out in children (Petrof et al., 2015; El-Darouti et al., 2016) and one in adults (Rashidghamat et al., 2020). In these trials two or three IV injections were administered over a 1-month period, without any HLA matching or preconditioning. Effects on wound healing, pain, and especially pruritus seemed to be rather promising, with only mild undesirable effects observed. The latter were mostly transient, and all were unrelated to MSCs. A major concern, however, has been the development of squamous cell carcinomas (SCC) in two out of 10 adult participants during the study period (Rashidghamat et al., 2020). Nevertheless, the causality of this serious event is still being debated, given that SCCs represent a naturally occurring complication of RDEB. No increase in C7 or anchoring fibrils at the DEJ could be detected in skin biopsies. The improvement in adhesion has been attributed to either an increased expression of other junctional adhesion proteins or a reduction in inflammatory mediators that impair DEJ adhesion. Optimizing the number and frequency of MSC infusions, while addressing specific MSC subpopulations like skin homing ATP-binding or cassette subfamily B member 5 positive (ABCB5) MSC (Riedl et al., 2021) are currently being studied and designed to improve the outcome results. Injection of MSC-derived anti-inflammatory products carried in exosomes (Perdoni et al., 2014; Shabbir et al., 2015; McBride et al., 2018) is similarly under investigation, as are HMGB1 and SDF1 able to attract MSC.

In principle, all genodermatoses are candidates for gene therapy (Ain et al., 2021).

The major obstacle to this process is the efficient, safe, and targeted delivery of the gene (Ain et al., 2021; Bustad et al., 2021). Non-integrating viral vectors like adenoviruses were the first to be applied and have so far been the most widely used. Nevertheless, they carry a restricted cargo potential, which may be a limiting factor for large genes such as NF1 (Walker and Upadhyaya, 2018). Besides, herpesviruses are commonly chosen for in vivo transfection. Retroviruses and the subgenus lentiviruses, as well, have the capacity to integrate into the genome, thereby allowing for stable and long-term gene expression, yet with a risk of being mutagenic at the insertion site.

Alternatives to viruses are lipid based nanoparticles (LNPs) and polymeric nanoparticles. These have the advantage of being able to overcome proteolytic degradation in the skin, while they are devoid of mutagenic risk and permit the transport of larger fragments. Moreover, electroporation, sonoporation, iontophoresis, and microneedles are physical methods that may be applied so as to deliver products into the cells (Ain et al., 2021).

Gene administration may be ex vivo, involving cells harvested from the patient. Gene administration can also occur in vivo while delivering the vector carrying the correct gene to the patient via transfusion. In the last case scenario, the vector must be designed with a specific tropism for the target organ. Another means of administration consist of in situ injection into tissues or topical application, such as on the skin (Papanikolaou and Bosio, 2021).