The ISG supports ichthyosis related research.
Updates for these projects can be found in individual posts about each of the projects, or alternatively click here.
The following explains where grants have previously been awarded and how they will be used to help research projects.
Individuals with Lamellar ichthyosis have extensive scaling that requires time consuming skin treatment each and everyday. If we understood why scaly skin occurs in individuals with Lamellar ichthyosis, we could devise better treatments that would reduce the amount of time taken everyday to treat the scaling. We are able to grow Lamellar ichthyosis skin in the laboratory, and using this we have found increased amounts of a protein called interleukin-1 alpha and decreased amounts of proteins that alter the ability of the lipids (fats) of the skin to act as a barrier to water loss.
There is a large range of Lamellar ichthyoses, ranging from severe scaling to the much milder self-healing forms of the disease. We intend to model the range of different Lamellar ichthyoses in the lab and determine whether the proteins we are interested in, such as the interleukin-1 alpha protein, are increased in all forms of Lamellar ichthyosis, making it a good potential target for future therapies.
Patients suffering from bullous congenital ichthyosiform erythroderma (BCIE) carry a mutation in either keratin 1 (K1) or keratin 10 (K10) protein. These two proteins act as partners and are, alongside other proteins, responsible for skin stability. If either K1 or K10 is defective, skin resilience is reduced. This causes blistering in infants which is later compensated by skin thickening and pronounced ichthyosis. There is no cure for the disease and retinoids used to reduce the ichthyosis in adult patients increase the blistering.
Research for this form of disorder aims to reduce the production of the defective keratin. The diversity of K1 and K10 mutations found in BCIE patients complicates a general treatment of the disease and demands patient-specific therapy addressing keratin mutations individually. One way to eradicate the need for individual therapies would be to eliminate the keratin pair K1/K10 altogether using a universal drug suitable for all patients irrespective of their specific mutation. The removed keratin pair could be replaced by another keratin pair (K5/K14) which also exists normally in skin.
The project aim is to establish whether the deletion of K1/K10 in skin can be fully substituted by the existing keratin pair K5/K14 which in turn may aid the development of a BCIE therapy to suppress the production of mutant keratins.
Gene Therapy for genetic skin disease Netherton syndrome
Netherton syndrome is a serious, life-threatening, genetic skin condition caused by mutations in the gene SPINK5. Patients with Netherton syndrome have “scalded-skin” at or soon after birth with other clinical features such as red skin, hair shaft defects, recurrent infections and susceptibility to allergies. There is a recognised mortality risk of 10% in the first 6 months of life in infants with Netherton syndrome due to life-threatening complications such as bronchopneumonia, sepsis and hypernatraemic dehydration secondary to severe water loss through the defective ‘skin barrier’, the outermost layers of the skin. Currently, there are no specific treatments for patients with Netherton syndrome except emollients to improve the compromised skin barrier. There is an urgent need to develop new therapies for this debilitating disease.
We have been developing new strategies to treat Netherton syndrome patients using gene therapy where correct SPINK5 gene is delivered into skin stem cells obtained from patients’ skin with this disease. These genetically corrected cells are then cultured as skin sheets in the laboratory and grafted back into patients. We have already completed proof-of-principle studies showing significantly corrected skin architecture in the genetically modified skin graft generated from Netherton syndrome patients’ cells.
At present, we are carrying out a further study to confirm whether the genetically modified grafts can provide not only an immediate local protective barrier, but also act as a ‘protein factory’ to continuously supply the corrected LEKTI, a SPINK5 gene corresponding protein, to whole body in a generalized effect. If this is possible, we hope to use small patches of skin grafts to treat Netherton syndrome patients. This would be of significant therapeutic benefit for patients with Netherton syndrome, especially for small infants.