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Pharmaceutics Oct 2021Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold... (Review)
Review
Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold great promise for dermatological disorders with high unmet need, for example, epidermolysis bullosa or pachyonychia congenita. Furthermore, the recent clinical success of clustered regularly interspaced short palindromic repeats (CRISPR) for genome editing in humans will undoubtedly contribute to defining a new wave of therapies. Like biologics, naked nucleic acids are denatured inside the gastrointestinal tract and need to be administered via injections. For a treatment to be effective, a sufficient amount of a given regimen needs to reach systemic circulation. Multiple companies are racing to develop novel oral drug delivery approaches to circumvent the proteolytic and acidic milieu of the gastrointestinal tract. In this review, we provide an overview of the evolution of the gene therapy landscape, with a deep focus on gene and oligonucleotide therapies in clinical trials aimed at treating skin diseases. We then examine the progress made in drug delivery, with particular attention on the peptide field and drug-device combinations that deliver macromolecules into the gastrointestinal tract. Such novel devices could potentially be applied to administer other therapeutics including genes and CRISPR-based systems.
PubMed: 34684016
DOI: 10.3390/pharmaceutics13101722 -
Pain Dec 2016We compared patterns of intraepidermal nerve fibers and mechanoreceptors from affected and unaffected plantar skin from patients with pachyonychia congenita (PC) and...
We compared patterns of intraepidermal nerve fibers and mechanoreceptors from affected and unaffected plantar skin from patients with pachyonychia congenita (PC) and control subjects. Plantar biopsies from 10 genetically confirmed patients with PC (with a mutation in KRT6A) were performed at the ball of the foot (affected skin) and the arch (unaffected) and were compared to biopsies from corresponding locations in 10 control subjects. Tissue was processed to visualize intraepidermal nerve fibers (IENF) (PGP9.5), subsets of IENF (CGRP, substance P, tyrosine hydroxylase), myelinated nerve fiber (neurofilament H, NFH), blood vessels (CD31), Meissner corpuscles, and Merkel cells (MCs). Structures were quantified using stereology or validated quantification methods. We observed that PC-affected plantar skin had significantly lower sweat gland innervation (sweat gland nerve fiber density) and reduced numbers of Meissner corpuscles compared to PC-unaffected or anatomically matched control skin. In contrast, Merkel cell densities and blood vessel counts were higher in PC-affected skin compared to either control or PC-unaffected skin. There were no differences in myelinated nerve fiber densities, SP, or CGRP between the groups. Pressure pain thresholds in PC-affected skin were lower compared to PC-unaffected and anatomically matched control skin. Additionally, MC densities in callused plantar skin from healthy runners with callus and one subject with a nonpainful palmoplantar keratoderma (AQP5 mutation) were similar to PC-unaffected and control skin consistent with callus alone not being sufficient to increase MC number. These findings suggest that alterations in PC extend beyond keratinocytes and may provide strategies to study neuropathic pain in PC.
Topics: Adult; Aged; Animals; Aquaporin 5; Biopsy; Female; Humans; Keratin-20; Keratin-6; Male; Merkel Cells; Middle Aged; Mutation; Nerve Fibers, Myelinated; Neurofilament Proteins; Pachyonychia Congenita; Pain Threshold; Peripheral Nervous System Diseases; Skin; Ubiquitin Thiolesterase
PubMed: 27776012
DOI: 10.1097/j.pain.0000000000000711 -
The British Journal of Dermatology Mar 2020
Topics: Humans; Pachyonychia Congenita
PubMed: 31648361
DOI: 10.1111/bjd.18630 -
Clinical and Experimental Dermatology Jun 2021Pachyonychia congenita (PC) is a rare autosomal dominant disorder featuring palmoplantar keratoderma, nail dystrophy, oral leucokeratosis, pilosebaceous cysts and natal...
BACKGROUND
Pachyonychia congenita (PC) is a rare autosomal dominant disorder featuring palmoplantar keratoderma, nail dystrophy, oral leucokeratosis, pilosebaceous cysts and natal teeth. PC results from dominant mutations in one of five genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17) encoding keratin proteins.
AIM
To delineate the clinical and genetic features of PC in a series of Israeli patients.
METHODS
We used direct sequencing of genomic DNA, and also used cDNA sequencing where applicable.
RESULTS
We collected clinical information and molecular data in a cohort of Israeli families diagnosed with PC (n = 16). Most of the patients were Ashkenazi Jews and had a family history of PC. The most common clinical findings were painful focal plantar keratoderma (94%) accompanied by nail dystrophy (81%), pilosebaceous cysts (31%) and prenatal/natal teeth (13%). In contrast to the high prevalence of KRT6A mutations in other populations, we found that KRT16 mutations were the most common type among Israeli patients with PC (56%). Most (77%) of the Israeli patients with PC with KRT16 mutation carried the same variant (c.380G>A; p.R127H) and shared the same haplotype around the KRT16 locus, suggestive of a founder effect.
CONCLUSION
The data gleaned from this study emphasizes the importance of population-specific tailored diagnostic strategies.
Topics: Cohort Studies; Female; Genetics, Population; Genotype; Humans; Israel; Male; Molecular Epidemiology; Mutation; Pachyonychia Congenita; Phenotype
PubMed: 33190296
DOI: 10.1111/ced.14509 -
Journal of the American Podiatric... 2023
Topics: Humans; Pachyonychia Congenita
PubMed: 37938900
DOI: 10.7547/22-078 -
Indian Journal of Dermatology 2015Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis characterized by hyperkeratosis affecting the nails and palmoplantar areas, oral leucokeratosis,...
Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis characterized by hyperkeratosis affecting the nails and palmoplantar areas, oral leucokeratosis, and cystic lesions. It is classically subdivided into two major variants, PC-1 (Jadassohn-Lewandowski syndrome) and PC-2 (Jackson-Lawler syndrome), according to the localization of the mutations in the KRT6A/KRT16 or KRT6B/KRT17 genes, respectively. We report a 9-year-old male patient with a history of thickened, discolored nails, raised spiny skin lesions all over the body since birth with focal plantar keratoderma and absence of natal teeth.
PubMed: 26538744
DOI: 10.4103/0019-5154.159665 -
Advanced Drug Delivery Reviews Sep 2021Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the... (Review)
Review
Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the branched structural possibilities of polymeric vectors, we have developed a gene delivery platform for the treatment of an incurable monogenic skin disease - recessive dystrophic epidermolysis bullosa (RDEB) - based on highly branched poly(β-amino ester)s (HPAEs). The screening of HPAEs and optimization of therapeutic gene constructs, together with evaluation of the combined system for gene transfection, were comprehensively reviewed. The successful restoration of type VII collagen (C7) expression both in vitro and in vivo highlights HPAEs as a promising generation of polymeric vectors for RDEB gene therapy into the clinic. Considering that the treatment of patients with genetic cutaneous disorders, such as other subtypes of epidermolysis bullosa, pachyonychia congenita, ichthyosis and Netherton syndrome, remains challenging, the success of HPAEs in RDEB treatment indicates that the development of viable polymeric gene delivery vectors could potentially expedite the translation of gene therapy for these diseases from bench to bedside.
Topics: Animals; Epidermolysis Bullosa Dystrophica; Gene Transfer Techniques; Genetic Therapy; Humans; Polymers; Skin Diseases, Genetic; Translational Research, Biomedical
PubMed: 34293384
DOI: 10.1016/j.addr.2021.113842 -
Journal of the American Academy of... May 2015Significant developments in the use of mammalian target of rapamycin (mTOR) inhibitors (mTORIs) as immunosuppressant and antiproliferative agents have been made. Recent... (Review)
Review
Significant developments in the use of mammalian target of rapamycin (mTOR) inhibitors (mTORIs) as immunosuppressant and antiproliferative agents have been made. Recent advances in the understanding of the mTOR signaling pathway and its downstream effects on tumorigenesis and vascular proliferation have broadened the clinical applications of mTORIs in many challenging disorders such as tuberous sclerosis complex, pachyonychia congenita, complex vascular anomalies, and inflammatory dermatoses. Systemic mTORI therapy has shown benefits in these areas, but is associated with significant side effects that sometimes necessitate drug holidays. To mitigate the side effects of systemic mTORIs for dermatologic applications, preliminary work to assess the potential of percutaneous therapy has been performed, and the evidence suggests that percutaneous delivery of mTORIs may allow for effective long-term therapy while avoiding systemic toxicities. Additional large placebo-controlled, double-blinded, randomized studies are needed to assess the efficacy, safety, duration, and tolerability of topical treatments. The objective of this review is to provide updated information on the novel use of mTORIs in the management of many cutaneous disorders.
Topics: Humans; Immunosuppressive Agents; Skin Diseases; Skin Neoplasms; TOR Serine-Threonine Kinases; Tuberous Sclerosis
PubMed: 25769191
DOI: 10.1016/j.jaad.2015.01.014 -
Indian Dermatology Online Journal 2017
PubMed: 28761853
DOI: 10.4103/idoj.IDOJ_253_16 -
Journal of the European Academy of... Sep 2020
Topics: Humans; Pachyonychia Congenita; Rosuvastatin Calcium
PubMed: 32236980
DOI: 10.1111/jdv.16393