WCD Spots – Prof. Eli Sprecher
An interview with Prof. Eli Sprecher, of the the Division of Dermatology at the Tel Aviv Sourasky Medical Center.
Prof. Eli Sprecher, MD, PhD, MBA, Professor and Chair, Division of Dermatology, Deputy Director General for R&D and Innovation at the Tel Aviv Sourasky Medical Center, introduces his keynote talk on Genetics of skin disease.
Eli Sprecher. Hello, my name is Eli Sprecher, I’m the head of the Division of Dermatology at the Tel Aviv Medical Center in Israel. Nice to see you all.
What does Genetics of Skin Disease mean?
ES. I think that we are slowly but surely starting to understand that there is nothing which is not genetic in nature. Why is one individual developing an infection and another one not when both have been exposed to the same source simultaneously, for example? This tendency is simply genetically determined. Why is one individual developing Pemphigus vulgaris, and another one not? This is because of the fact they are carrying different genetic variations, which therefore imply different susceptibility, which are genetically determined to develop the disease. But I would like to paraphrase a classical quote: “all diseases are in fact genetic in nature, but
some are more genetic than others”, meaning that in some cases genetic variations are more likely to result in a disease phenotype. These are the diseases classically narrated in a Mendelian fashion. Just to give you an example: a patient with Keratoderma Striata, for example, will always transmit the disease to 50% exactly of his offspring; a patient with a genetic variant, which is associated with psoriasis, has a higher, but always very small and variable chance to develop the disease as compared to an individual who does not carry the genetic variant. This is a disease which is also genetically determined, but it is usually not considered as classical or traditional genetic skin disease
What are the most common types worldwide?
ES. Now, not all diseases which are genetic in nature have the same prevalence, and actually common hereditary skin diseases include, for example, Ichthyosis vulgaris. But even Ichthyosis vulgaris, which is a very common disease, has a different prevalence. For example, according to the region where the patient is living, Ichthyosis vulgaris will be very often much more visible in dry and cold climates, and are also diseases which can be more common, depending upon the patient origin or culture. For example, recessive disorders such as Junctional epidermolysis bullosa are usually much more common in populations characterized by high rate of consanguineous unions. And in some cases, the severity of a certain disease can also vary depending upon exposure to external factors. For example, we spoke about Keratodermas, so inherited Keratodermas will always be more severe in patients working physically.
What are the chances of preventing or combating a Genetics of Skin Disease?
ES. Simply lifestyle can be modified. Some diseases, as we just mentioned a minute ago, can be exacerbated by hot weather, for example, such as Epidermolysis bullosa simple, so we have to recommend to your patient to avoid hot weather. And in some cases, a disease is making the patient more susceptible to some complications and those can be avoided or at least identified and managed very early on. For example, Hypohidrotic ectodermal dysplasia is associated with a high risk of heat stroke when children with that disease are exposed to hot temperature, so you have to warn the family about that complication, which can be avoided. And children with Keratitis-ichthyosis-deafness syndrome, the KID syndrome, who have a tendency to develop squamous cell carcinoma, which can be very aggressive, those individuals have to be put under a very strict surveillance program so that cancer can be identified very early and managed also very early. And thereby, you can prevent complications, in this case early metastasis, for example. Now in some cases, non-specific therapies can also be helpful. All therapies, traditional therapies, for example, most disorders of cornification will respond to treatment with retinoids. And some of those disorders, by the way, can be exquisitely sensitive to retinoid therapies, such as, for example EKV, Erythrokeratodermiavariabilis. But apart from those non-specific interventions, there are today more and more of those more specific interventions. And just as an example, we can speak about drugs. Drug treatment, specific drug treatment, is also becoming a reality over the past years. In some cases, we will offer our patients drugs that have been specifically developed, specifically designed for their disease. And a nice example for that is Vismodegib, which was originally developed for treating
patients with Nevoid basal cell carcinoma syndrome. And in other cases, drugs used in general for other diseases can be repurposed to treat genetic skin diseases. For example, Gentamicin, that’s an antibiotic which is known to all of us as dermatologist. Gentamicin can also be used in order to push the translational machinery across of mutation and restore the biosynthesis of almost normal protein. This has been actually discovered in the context of many diseases and Gentamicin has been used, administered in a systemic fashion. But this drug can also be used topically successfully in order to treat genetics skin diseases because of course, skin diseases are amenable to topical treatment. And of course, those genetic diseases which are amenable to topical treatment with Gentamicin are caused, must be caused by nonsense mutations by stop mutations. And this treatment has been used successfully over the past few years in order to treat many, many different genetic diseases of the skin, including various forms of Epidermolysis bullosa, Palmoplantar keratoderma, Hypertrichosis, and even Hailey-Hailey disease.
In 2022, what is the scientific approach to Genetics of Skin Disease?
ES. Well, there are today many, many novel approaches to the treatment of those genetic diseases. Not only can drugs be repurposed, for example, but technologies can be as well. Let’s take for example Botulinum toxin, which of course is widely used in order to treat medical conditions as well as cosmetic conditions. This disease was recently found to be extremely useful in order to treat a specific form of Keratoderma, in the context of a genetic skin disease, Pachyonychia congenita. In this disease, patients are affected by a very, very painful form of Keratoderma: they cannot walk, they are very often confined to a wheelchair. And this, is most probably due to the accumulation of fluids, the calluses, which characterizing the source of those patients. So, Botox is now being used by intra-regional injection into the plantar skin and thereby preventing accumulation of fluid and effectively restoring the ability of those patients to walk and even sometime exercise, in other words, very, very dramatically improving their quality of life. There are also novel therapies, which can be called, or which are known under a kind of general umbrella term, cell therapies. Here we are exploiting the properties of special cell populations in order to alleviate disease manifestations. Those mesenchymal stem cells, for example, are being used in order to treat chronic wounds, including those encountered in the context of various forms of EB. We are also repurposing bone marrow transplantation in order to treat diseases like Epidermolysis bullosa where cells present in the bone marrow are migrating to the cells in the context of Dystrophic epidermolysis bullosa are restoring the ability of the skin to generate collagen 7 and thereby alleviate the manifestation of the disease. And of course, we are also now starting to understand the benefit of gene therapy, which is usually performed ex vivo: we are taking cells from the patients, mainly this has been mainly achieved in the context of Epidermolysis bullosa, correcting the defect found in the cells ex vivo, and then regrafting those cells to the patients with quite impressive results.
What is the state of research? And the possible future scenarios?
ES. So, first of all, we were speaking a moment ago about gene therapy ex vivo, but of course this is quite cumbersome kind of technique: you have to take out the cells ex vivo, correct the cells ex vivo, grab the cells back. That’s not an easy task. So instead of that, there are today’s technologies which are actually incorporating the normal gene into vectors, such as, for example, and this has been also recently published into an HSV, Herpes Simplex Virus vector, which is, of course, a non-pathogenic vector. And the vector is actually carrying in the form of cream, the normal gene into the skin. That’s much more practical, of course, than performing gene therapy ex vivo. There are also many technologies which are now being used in order to improve drug delivery into the skin. For example, we know today that for some form of very severe Palmoplantar Keratoderma such as in the context of Olmsted Disease, EGFR inhibitors, which of course are very well known to all of us in the context of oncological conditions. Erlotinib, for example, one of those EGFR inhibitors, can be used in order to treat Palmoplantar Keratoderma. But of course, the drug has to be given orally with a lot of side effects. So it would be, of course, very much desirable to be able to deliver this drug topically. There are a lot of problem with drug delivery, this is now being solved using a number of technologies which are either based on the use or the clever use of the various laser technologies and other high-end techniques as well. There are also more and more of those small molecules which are targeting defects causing genetic skin diseases, and those small molecules are increasingly being de discovered using high throughput approaches where hundred and sometime thousand and sometime hundreds of thousands of small molecules are being screened in order to find the one molecule which is capable of correcting the defects causing a genetic skin disease. So, biologicals and small molecules will not only be used in order to treat inflammatory diseases as we have been used over the past few years, but also in order to try to alleviate the clinical manifestations of the genetic skin diseases as well. And finally, we have more and more of those technologies which enable us to re-engineer the biology of specific cells. And those cells are actually transformed into small plants, which can be delivered in order to, for example, generate a missing protein, in the circulation, an enzyme missing an enzyme inhibitor such as, for example, in Nettleton syndrome, missing and causing sometime very, very dreadful diseases. These are, of course, things that we will more and more see in the future.
Just before closing, we need of course to remember that, still today, the best treatment we can offer to families affected by genetic skin diseases is prevention, using prenatal diagnosis. But this is of course also very often associated with invasive technologies, to which sometime patients are reluctant to turn to those techniques, to those approaches.
Now, wealso have to turn an eye on novel non-invasive prenatal testing, what is called NIPT or non-invasive prenatal testing technologies, which are capable of identifying mutation during embryonic development, in the circulation of the model. And this is, of course, something which is going to be more and more available over the next few years and will very much simplify the way we can now effectively, efficiently, prevent genetic skin diseases to develop.
ES. So, with this, I’d like to wish you all the very best and I am waiting very much to see you all in Singapore for the World Congress of Dermatology. Goodbye.
