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Gene & Protein in Disease Gene therapy progress for DEB

of skin cleavage and genetic mutation: EB simplex, both alleles, leading to either degradation of nonsense
2,3
junctional EB, dystrophic EB (DEB), and Kindler EB. DEB mRNA or partial expression of truncated C7 polypeptides
is characterized by a plane of cleavage just beneath the that are subsequently degraded within the cell. The
lamina densa in the most superficial portion of the dermis skin of RDEB patients is typically observed to lack AFs.
and is caused by mutations in the COL7A1 gene, which can Symptoms and complications of RDEB include lesions
be inherited in a dominant or recessive manner. and blistering, anemia, nail dystrophy and loss, milia,
infections, musculoskeletal contractures, strictures or
All subtypes of EB are considered rare disorders
without observable differences in prevalence and incidence stenoses, constipation, malnutrition/nutritional problems,
pseudosyndactyly, ocular manifestations, and dental
rates across sex or ethnic groups. The prevalence and caries. Individuals with severe RDEB are at a significantly
6,14
incidence of all subtypes of DEB by 2002 were reported elevated risk of developing squamous cell carcinoma, with
as 0.42/1 million population and 1.48/1 million live births, an incidence rate as high as 76%. This type of skin cancer is
respectively. More recently, in England and Wales, the associated with a mortality rate of up to 84% by the age of
4
prevalence and incidence of DEB were calculated as 10.7 40. Patients diagnosed with DEB exhibit a reduced quality
15
and 26.1, respectively. Since the incidence of DEB was of life accompanied by a decline in functional abilities and
5
analyzed based on data obtained from patients enrolled social activities, as well as increased pain and pruritus.
16
in clinics, the results are heavily influenced by the patient Families of patients with RDEB have reported experiencing
recruitment and observation length, resulting in the negative impacts on private life for 79%, and high rates of
different incidences between countries, particularly for financial burden for 50 – 54% of families. Medical costs in
data from undeveloped countries. Eichstadt et al. used Ireland amounted to $84,534/year, and estimated annual
7
6
a genotypic modeling approach to estimate the allele expenses for wound dressings in the United States ranged
frequency of pathogenic variants, from which the incidence from $4,000 to $245,000. 15
of recessive DEB (RDEB) was 30 times higher than the
incidence reported in 2016 by the National Epidermolysis To date, palliative interventions, such as bandaging of
Bullosa Registry. These estimates of DEB prevalence, the skin and nutritional support, remain the mainstays of
4
derived from either clinical data or modeling calculations, treatment for DEB. 15-19 Despite the ongoing development
provide an indication of the number of patients with DEB of advanced therapeutics (Figure 1), including cell
who would benefit from COL7A1-directed therapies. therapy, 20-23 protein replacement therapy, 24-27 gene
replacement therapy, 28-34 RNA regulation therapy, 35-38
Mutations in the COL7A1 gene have been documented and gene editing therapy, 39-46 it is crucial to continue
in the Human Gene Mutation Database (https://www. efforts to develop therapeutic approaches and improve
hgmd.cf.ac.uk/), where a total of 878 mutations were the quality of life for DEB patients. Gene therapy holds
recorded up to April 2023. This number is likely to promise for providing targeted therapeutic approaches to
increase, as ongoing research and genetic testing continue treat and potentially cure diseases. This review provides a
to discover new mutations. The expression of the comprehensive overview of the current COL7A1 genetic
COL7A1 gene is tissue-specific and exhibits a restricted engineering strategies being developed for DEB. It
pattern. Specifically, type VII collagen (C7) expressed critically evaluates the significance and progress of animal
from COL7A1 has been detected by immunostaining in models in DEB research, which are essential for assessing
several epithelial tissues, including human skin, corneal therapeutic approaches. Furthermore, it discusses the
epithelium, and gastrointestinal mucous membranes. existing challenges and highlights recent advancements in
8,9
C7 is a crucial protein that forms anchoring fibrils (AFs) gene therapy for DEB, offering valuable insights to inform
for connecting the dermis and epidermis. The correlation future research and clinical practices.
between genotype and phenotype has been extensively
investigated for the major subtypes of DEB, with mutations 2. Gene therapy for DEB
primarily affecting the expression, stability, and formation Gene therapies involve replacing a non-functional gene
of C7 and AFs. 8-13
with a functional healthy gene, inactivating disease-causing
There is a wide range of COL7A1 mutations and genes, or introducing new or modified genes into the body.
numerous families possess unique mutations. Various Due to its monogenic nature, DEB is an ideal candidate
combinations of mutations produce a spectrum of for gene therapy. The isolation and cloning of COL7A1
biological characteristics, which account for the diverse complementary DNA (cDNA) have significantly advanced
clinical severity and overlap among different forms of our understanding of the structure and function of C7 as
DEB. In cases with the most severe form, RDEB, COL7A1 well as the pathogenesis of DEB, thereby promoting the
14
mutations result in premature termination codons in development of gene therapy for DEB through genetic

Volume 3 Issue 3 (2024) 2 doi: 10.36922/gpd.4047