An appealing step closer to targeted topical therapies

By Warren R. Heymann, MD, FAAD
April 5, 2023
Vol. 5, No. 14

Although advances in molecular genetics have revolutionized our understanding of the pathogenesis of disease, the road to developing topical therapies based on these discoveries is in its infancy.

Healthy maintenance of our stratum corneum is essential to life. Alterations in the precise, intricate dance of corneocyte production and desquamation may lead to diseases ranging from mild forms of acral peeling skin to profound disorders such as Netherton syndrome. According to Has: “Epidermal desquamation consists of the gradual invisible shedding of corneocytes from the outermost layers of the stratum corneum through controlled degradation of corneodesmosomes, the major cell–cell junctions in the stratum corneum. Corneodesmosomes consist mainly of transmembrane proteins DSG1 [desmoglein], DSC1 [desmocollin], and CDSN [corneodesmosin], which are anchored at cell peripheries through extensive enzymatic cross-linking mediated by TGM1 [transglutaminase], TGM3, and TGM5. Degradation of corneodesmosomes is tightly regulated through the interplay between proteases and their inhibitors. Under homeostatic conditions, DSG1, DSC1, and CDSN are cleaved by serine proteases (kallikreins) and cysteine proteases (cathepsins), which are under the control of protease inhibitors. Increased degradation of corneodesmosomes caused by primary structural defects (i.e., CDSN or DSG1 deficiency), by imbalances between protease and their inhibitors (i.e., LEKTI, CSTA, CAST, or SERPIN8 deficiency), or by other factors (e.g., bacterial toxin, autoantibodies, and drugs) leads to accelerated desquamation in the form of skin peeling.” (1)

Under the umbrella of autosomal recessive congenital ichthyosis (ARCI) are the peeling skin syndromes (PSS) caused by defective cell-to-cell adhesion in the upper epidermis. PSS localized to the extremities is termed acral PSS and usually caused by mutations in the TGM5 gene encoding transglutaminase 5 (although mutations in the CSTA gene, encoding cystatin A, have also been shown to be causative). Generalized PSS can result from pathogenic variants in FLG2, encoding filaggrin 2 or from mutations in CDSN, usually associated with significant inflammatory manifestations. (2) Please refer to table 1 in Has’s manuscript (reference 1) that elaborates the cutaneous features, associated features, and affected gene/protein for localized PSS, generalized noninflammatory PSS, and generalized inflammatory PSS. (1)

To date, therapy for PSS primarily involves symptomatic control with topical emollients and avoidance of aggravating factors such as heat, humidity, and friction. (3) Intravenous lipid infusion (Vitalipid, an emulsion of fat-soluble vitamins) was reported to be effective in treating a rare form of PSS, the PLACK syndrome (Peeling skin, Leukonychia, Acral punctate keratosis, Cheilitis, and Knuckle pads). (4) PLACK syndrome is an autosomal recessive genodermatosis caused by pathogenic mutations in CAST, which encodes calpastatin, an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. (5) Intralipid therapy was utilized because the syndrome is associated with low levels of vitamin A and essential fatty acids. (4)

PSS type1 (PSS1, OMIM 270300) is a rare autosomal recessive disorder caused by nonsense mutations or complete deletion of the CDSN gene encoding for CDSN. Patients may exhibit pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin. PSS1 severely impairs quality of life and therapeutic approaches are uniformly unsatisfactory. Valentin et al sought to take the first steps toward developing a specific protein replacement therapy for CDSN deficiency in order to improve cell-to-cell cohesion in the transition area of the stratum granulosum (SG) to the stratum corneum. Human CDSN was recombinantly expressed in Escherichia coli. A liposome-based carrier system, prepared with a cationic lipopeptide to mediate the transport to the outer membrane of keratinocytes, was developed for delivery into the skin. The liposomes showed an accumulation at the membranes of keratinocytes. CDSN-deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG. The authors demonstrated that the penetration assay and histological examinations revealed improved epidermal integrity for CDSN-deficient epidermal equivalents if they were treated with liposomal encapsulated CDSN. The authors speculated that this technology may not only benefit patients with PSS1 but could be useful for other disorders such as Netherton syndrome or atopic dermatitis. (6)

Every dermatologist understands the potential appeal of effective, specific topical therapy for ARCI and PSS. It is scintillating to realize that we are on the cusp of having such creams developed.

Point to Remember: A liposomal formulation of recombinant corneodesmosin has shown efficacy for peeling skin syndrome type 1 in vitro. Perhaps targeted topical replacement creams will no longer be in the realm of science fiction.

Our expert’s viewpoint

Patrick J. McMahon, MD, FAAD
Dermatologist, Associate Professor of Medicine
Cooper Medical School of Rowan University

Liposomal encapsulated, recombinantly expressed human corneodesmosomes derived from E. coli have been successfully delivered to the membranes of keratinocytes?! For Peeling Skin Syndrome and various forms of ichthyosis, this kind of futuristic-sounding treatment option could revolutionize the way we treat patients. If we can have access to disease-modifying therapies as opposed to our current list of mostly supportive treatments I can imagine having more hopeful conversations with patients and families suffering with disorders of cornification. Furthermore, this kind of targeted therapy option could be useful in external creams to replace defective or missing proteins in the skin could have implications for a whole host of genetic skin conditions from epidermolysis bullosa to the vast array of genodermatoses such as Darier’s Disease or Hailey-Hailey Disease. I can even imagine that if a durable replacement protein could be engineered and delivered safely and accurately to its desired destination in the human body, we could have a potential to modify or cure diseases well beyond rare dermatological conditions.

However, before we get too ahead of ourselves and speculate on how we may be able to scientifically modify diseases with microscopically transported proteins there are some serious logistical barriers to this kind of treatment as it advances from in vitro to in vivo. As I see it, these barriers include transportation of the molecules in human skin, tolerability of the treatment, duration of response, cost, and unintended side effects, among others. Tolerability of this therapy would encompass whether burning or irritation occurred from the treatment itself or the vehicle. Is it practical to apply this treatment and, if so, how frequently is that application required? Will the response be durable? For diffuse conditions like ichthyosis will it require application of a cream to the entire body several times daily? Human trials will help elucidate these kinds of issues and hopefully identify other potential side effects. For new medications, cost will almost always be a hurdle, but in time that hurdle may be overcome if manufacturing can become more affordable.

Nonetheless, targeted treatments are certainly an exciting new area of exploration within dermatology and beyond. Targeted gene-therapy has improved vision for patients with Leber congenital amaurosis, a form of congenital blindness — although each treatment is currently costing approximately $500,000 per eye per treatment. As we look in our crystal balls of medical therapeutics, I am cautiously optimistic that targeted therapies like this will become a reality and dramatically change the way we impact dermatologic conditions. We just may need to start by peeling back one layer at a time until treatments can successfully penetrate the full thickness of cutaneous pathologies.

1. Has C. Peeling Skin Disorders: A Paradigm for Skin Desquamation. J Invest Dermatol. 2018 Aug;138(8):1689-1691. doi: 10.1016/j.jid.2018.05.020. PMID: 30032785.

2. Mohamad J, Nanda A, Pavlovsky M, Peled A, Malchin N, Malovitski K, Pramanik R, Weissglas-Volkov D, Shomron N, McGrath J, Sprecher E, Sarig O. Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis. Exp Dermatol. 2020 Aug;29(8):742-748. doi: 10.1111/exd.14140. Epub 2020 Jul 20. PMID: 32618001.

3. Schimmel J, Renzi M, Fawaz B, Halpern A. Painless erosions on the hands and feet of a 7-year-old boy. Pediatr Dermatol. 2020 Mar;37(2):371-372. doi: 10.1111/pde.14082. PMID: 32196738.

4. Sawan ZA, Almehaidib A, Binamer Y, Monies D, Alsaleem KA, Aldekhail W, Alkuraya FS, Abanemai M. PLACK syndrome is potentially treatable with intralipids. Clin Genet. 2021 Apr;99(4):572-576. doi: 10.1111/cge.13919. Epub 2021 Jan 20. PMID: 33410500.

5. Boggs JME, Irvine AD. PLACK syndrome resulting from a novel homozygous variant in CAST. Pediatr Dermatol. 2021 Jan;38(1):210-212. doi: 10.1111/pde.14383. Epub 2020 Oct 3. PMID: 33010050.

6. Valentin F, Wiegmann H, Tarinski T, Nikolenko H, Traupe H, Liebau E, Dathe M, Oji V. Development of a pathogenesis-based therapy for peeling skin syndrome type 1. Br J Dermatol. 2021 Jun;184(6):1123-1131. doi: 10.1111/bjd.19546. Epub 2020 Nov 2. PMID: 32926582.

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