What is Gene Therapy and Is the Skin Suitable for Gene Therapy?

Since its first discovery, conceptualization in 1972, and successful application in 1990 by W. French Anderson, gene therapy has been a revolutionary game-changer in the field of biotechnology and healthcare. Now, its scope reaches beyond autoimmune disorders or cancer treatment, and potential genetic therapies are observed to be successful in treating several conditions related to dermatology too. Dermatological treatments are evolving from purely topical medications to include oral treatments, injectables and light and laser therapies. Gene therapies proffer a different tangent to address the cause of the disease, rather than providing just symptomatic care. Although still in extremely early stages, gene therapy is offering some promising solutions that were previously considered incurable in the field of rare genetic dermatology diseases. 

Ongoing research is proving that the skin possesses few qualities that make it desirable for gene therapy, it is easily manipulatable, superficial, and a versatile organ. The dermis is a highly vascular structure with the ability to synthesize and secrete a lot of proteins in the circulation which makes it extremely suitable for gene therapy. Being the largest organ present in the human body, skin is easily accessible for gene delivery and it has a strong regenerative capacity.

Other than genetic diseases, important advancement has been made in the treatment of other skin diseases like skin cancer, skin wounds, and intractable inflammatory skin diseases. If the skin is transduced with the transgene of transferrin erythropoietin, growth hormone, apolipoprotein E, and factor IX,  it secretes the gene product in circulation and its physiological effect can be enormous.

There are many factors that make the skin a desirable target for gene therapy; still, there are no FDA approved gene therapies for any dermatologic indications. 

Gene Therapy for Skin Diseases

Vectors in gene therapy are used to introduce genetic material into cells to alter gene expression, negating a pathological process. This can be accomplished with a variety of viral vectors or nonviral administrations.  Due to the comparative ease of gene transfer, skin diseases become a favourite target of gene therapy.

Although results are promising, there are still several potential pitfalls that must be addressed to improve the safety profile to make gene therapy for skin diseases widely available clinically. Unfortunately to this date, the therapy is experimental and not yet in regular use. Skin cancer, chronic wound, and intractable inflammatory disease can also be treated by gene therapy.

A few of the major dermatology diseases that have the potential to be treated by gene therapy are as mentioned:-

Inherited Skin Disorders

Epidermolysis bullosa 

Epidermolysis bullosa is a group of rare genetic medical conditions, where blisters are formed on the skin and mucous membranes. These blisters can be extremely painful and their severity range lies from mild to fatal. EB is generally caused by mutations involving at least 18 genes encoding structural proteins within keratin intermediate filaments, focal adhesions, desmosome cell junctions, and hemidesmosome attachment complexes, which form the intraepidermal adhesion and dermo-epidermal anchoring complex within the basement membrane zone (BMZ) of the skin and mucosae.

According to DelveInsight, the total prevalent population of Epidermolysis bullosa in 7MM ranges was 41,509 in 2017 and the total diagnosed prevalent cases of EB were 39,433 which indicates how rare Epidermolysis bullosa is.

One of the most common questions asked is can Epidermolysis bullosa be cured

There are no Epidermolysis bullosa-specific medications, depending on the severity of the condition, doctors may recommend over-the-counter pain medication or may prescribe stronger painkillers, such as morphine. All the types of Epidermolysis bullosa are characterized by fragile skin and a range of cutaneous involvement from blistering, usually on the hands and feet, to more generalized wounding. In addition to wound management, optimizing nutrition and dental health, minimizing deformity, ophthalmic complications, and genitourinary problems are also taken care of. Antihistamines, gabapentin, pregabalin, TCA, serotonin-norepinephrine uptake inhibitors (SNRIs), and other nontraditional antipruritic agents are considered for itch treatment.

A significant percentage of Epidermolysis bullosa cases develop aggressive squamous cell carcinoma. So the benefit of gene therapy outweighs the risk associated with it, especially considering the fact of unavailability of any acceptable therapy.

There are three main subtypes of Epidermolysis bullosa: EB simplex (EBS), junctional EB (JEB), and dystrophic EB (DEB), which are caused by various mutations and penetrate at different levels of the skin.

Epidermolysis bullosa simplex (EBS)

What is Epidermolysis bullosa simplex? 

Epidermolysis bullosa simplex is a genetic skin disease that causes blisters on the skin and is associated with defective gene expression of the basal keratinocyte. 15 genes and 13 proteins are accountable for the specific subtype of this disease. KRT5 and KRT14 keratin genes are affected in this condition caused by a dominant mutation. A recent study indicated that Epidermolysis bullosa simplex is affecting around 1 in every 20,000 children born in the USA, making EBS, one of the most experimented with gene therapy in dermatology conditions.

As per DelveInsight’s analysis, there were 14,879 cases of Epidermolysis bullosa simplex in 2017 in the United States and the majority of Epidermolysis bullosa cases in the United States consist of Epidermolysis bullosa simplex (EBS). 

Treatment of Epidermolysis bullosa simplex consists of Oligonucleotide mediated gene correction technique is used to correct KRT 14 gene, AAV gene-targeting vector with promoter trap design technique and other gene therapies like antisense technology and RNA interface have also shown good efficacy results. New Jersey-based Castle Creek Pharmaceuticals is developing and commercializing gene therapy for rare skin diseases.

Junctional epidermolysis bullosa (JEB)

Another subtype of Epidermolysis bullosa, Junctional epidermolysis bullosa (JEB) also causes the affected person’s skin to be extremely fragile and form blisters easily. JEB has been divided into two types – Herlitz (H-JEB) and non-Herlitz (NH-JEB) types.

How common is Junctional epidermolysis bullosa?

According to DelveInsight’s estimates, there were 1,240 cases of  Junctional epidermolysis bullosa in the United States in 2017. This disease is usually identified at birth but may be apparent after a few years. It can lead to increased vulnerability to infections and loss of body fluids. The moist lining of the mouth and digestive tract appears to be covered from blisters and wounds are formed over large regions in the body. 

Three genes that encode for epithelial basement membrane are LAMA3, LAMB3, and LAMC2 among which the LAMB3 gene is genetically mutated in the case of Herlitz Junctional epidermolysis bullosa  (H-JEB). Retroviral vector has been found as the vector with the most efficacy in H-JEB treatment. Non-viral vector called ΦC31 integrase is another potential genetic therapy.

Junctional EB has been also corrected via an ex-vivo technique using a human skin graft/immune-deficient mouse xenograft model. Nearly 80% clinical correction was achieved with a genetically modified skin graft in the patient with Junctional epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB)

Dystrophic epidermolysis bullosa is one of the major forms of epidermolysis bullosa. The signs and symptoms can vary widely among affected people. In mild cases, blistering may primarily affect the hands, feet, knees, and elbows. Severe cases often involve widespread blistering that can lead to vision loss, disfigurement, and other serious medical problems. 

DelveInsight estimates that there were 8,680 cases of Dystrophic epidermolysis bullosa in the USA in 2017.

Dystrophic epidermolysis bullosa occurs due to mutations in the gene (COL7A1) encoding for type VII collagen (C7). It may be of two types – dominant and recessive. Recessive Dystrophic epidermolysis bullosa can at times lead to severe complications like scarring, mitten deformity of hands and feet, and early death due to sepsis or even may lead to aggressive squamous cell carcinoma. 

Emerging gene therapy constitutes potential Dystrophic epidermolysis bullosa treatment such as EB-101 by Abeona Therapeutics is autologous, gene-correcting cell therapy, Krystal Biotech is studying a topical gel that uses a herpes simplex viral vector to deliver COLA7A1. Another breakthrough therapy developed by RegeneRx is RGN-137, a topical gel formulation of the peptide Tβ4, as a novel treatment to accelerate dermal wound healing and Fibrocell Science is utilizing a lentiviral vector to modify autologous fibroblasts, which are then injected intradermally.

Pachyonychia congenita

What is Pachyonychia congenita

It is a rare genodermatosis associated with mutation of the keratin gene resulting in painful plantar keratoderma, primarily affecting skin and nails. The signs of this disease are visible a few years after a child’s birth.

It is estimated that 5000-10,000 prevalent cases of Pachyonychia congenita were reported in January 2020.

There are 2 types of Pachyonychia congenita diseases observed – Pachyonychia congenita Type 1 is a disorder caused due to mutation of gene encoding keratin 6A/KRT16; whereas Pachyonychia congenita Type 2 disease is due to mutation of gene encoding keratin 6B/KRT17. There is no definitive or curative treatment for Pachyonychia congenita and the therapies only target symptomatic relief to decrease bothersome manifestations of the disease. Because of Pachyonychia congenita’s high rarity, there is an absence of data collection and information associated with the disease making it more difficult for researchers to study for the treatment.

Currently, gene therapy is considered as the only viable alternative for Pachyonychia congenita cure and there is an ongoing double-blind phase-1b study using siRNA as a prospective future therapy. It was initiated on one subject for 17 weeks. Here, one foot was administered with siRNA injection, and the other with vehicle injection. On the siRNA injection affected foot, regression of calluses was observed with tenderness and without any adverse effect except pain at the site of injection. But the condition reversed after stopping the therapy.

Netherton syndrome

Another genetic disorder, Netherton syndrome, is caused by the mutation of a gene – SPINK5 located on chromosome 5 – responsible for encoding proteins that serve as the break on the activity of certain proteases in the skin protein. This results in affecting the skin, hair and immune system of patients. Sometimes red and scaly skin is observed in the newborns and other times the skin may also leak fluids. Netherton syndrome is a rare disorder that is inherited as an autosomal recessive trait. 

As per Delveinsight estimates, the United States had the highest Netherton Syndrome prevalence in the year 2020. And the total prevalent population of Netherton Syndrome in the 7MM countries was estimated to be 3,411 cases in 2020.

Over the past years, Netherton syndrome cure has not yet evolved; current approaches are all limited to symptomatic relief or supportive care with marginal efficacy and undesirable side effects. A gentle, soft non-detergent liquid cleansing oil, preferably with an acidic pH (5) to counteract overactive serine proteases, is recommended for daily bath and/or shower. Liberal use of bland emollients along with topical corticosteroids and calcineurin inhibitors for inflammatory skin lesions is also advised. Key companies working predominantly in the molecule targeting field to treat Netherton syndrome include Novartis (LM 030), Timber pharmaceuticals (Isotretinoin), Bridge Biopharma, Evotec AG, and Dermelix Biotherapeutics.

Xeroderma pigmentosum

Xeroderma pigmentosum is a very rare genetic disorder in which affected patients suffer from inefficient nucleotide repair (NER) due to ultraviolet ray (UV) induced mutations in their DNA. Nucleotide repair is the most efficient DNA repair system, so defects in this culminates in serious mutagenesis and finally skin cancers in most, even before 30 years of age. It is so rare that it affects 1 in a million people in the 7MM, as estimated by DelveInsight.

Xeroderma pigmentosum treatment includes deriving retrovirus from murine leukaemia viruses (MMLV) which is used to correct the nucleotide repair mechanism of keratinocyte DNA repair. On exposure to UV radiation, the corrected keratinocytes continue to repair DNA properly. Corrected keratinocyte holoclones also appear to convey long-term DNA repair while maintaining their DNA repair capabilities.

Adenovirus-mediated transduced fibroblast is also used to correct DNA repair XP gene therapy. Plasmid DNA vector should be used in the management of Xeroderma pigmentosum, to avoid the risk of insertional mutation.

Sjogren-Larsson syndrome (SLS)

Sjogren-Larson syndrome is an inherited disorder developed due to the mutation of the ALDH3A2 gene, which encodes the enzyme fatty aldehyde dehydrogenase (FALDH). It usually gives rise to scaling of the skin, mental retardation, spasticity, speech abnormalities, and at times seizures too. Fine scales with deeply reddened skin are easily distinguished in newborn babies affected. Sjogren-Larson syndrome affects 1 in 2.5 million people in the 7MM.

Sjogren-Larson syndrome treatment includes topical application to the affected area for a sense of relief but they are not curative. Zileuton is another potential symptomatic therapy. But in recent years, genetic therapy involving a recombinant AAV2 vector is used to transduce Sjogren-Larson syndrome keratinocyte, resulting in normal FALDH expression by phenotypically normal keratinocyte which may act as a possible treatment for this rare, hereditary disease.


Ichthyosis is a commonly caused genetic mutation that is inherited from either one or both parents. Ichthyosis causes fish-scale like a skin condition. This disorder results in thick, rough and dry skin which needs to be moisturized or hydrated frequently. The most common forms of inherited Ichthyosis are mild, and they might improve during warm climates, aslo some forms can be severe and life-threatening as well. There are five distinct inherited ichthyosis types which include ichthyosis vulgaris, lamellar ichthyosis, epidermolytic hyperkeratosis, congenital ichthyosiform erythroderma, and X-linked ichthyosis.

Ichthyosis is a common dermatology disease affecting 1 in 300 childbirths according to an analysis by DelveInsight. Currently, there is no cure for Ichthyosis, only moisturizing and exfoliating the skin act as symptomatic relievers. Scientists are looking for an Ichthyosis cure in genetic therapy products.

Lamellar Ichthyosis

What causes Lamellar ichthyosis

It is a recessive and rare genetic disorder, where skin cells are produced at a normal rate, but they do not separate normally at the surface of the outermost layer of skin and are not shed as quickly as they should be which leads to the formation of scale. The signs and symptoms of Lamellar Ichthyosis differ from individual to individual. Some have mild signs and symptoms, while for others it might be severe.

According to an estimate by DelveInsight the total prevalent cases of Lamellar Ichthyosis in the 7MM were found to be 4,038 in 2017.

Currently, there is no approved Lamellar Ichthyosis medication, however, off-label therapies like retinoids, emollients, and keratolytic are available for symptomatic treatment like removal of scales. The general treatment course is aimed at controlling symptoms with exfoliating creams and ointments application being found to be crucial.

To treat the symptoms related to Lamellar ichthyosis, gene therapy may also prove to be helpful. Almirall and Tyris Therapeutics have entered a strategic partnership to develop non-viral gene therapies to aid in several orphan dermatological conditions.

Sterna Biologicals is developing an anti-GATA3 gene therapy product to treat Atopic dermatitis, Eczema and other related symptoms.


Porphyria is a disorder of the hematopoietic system where an extreme build-up of porphyrin takes place inside the body due to natural chemicals. They are a type of inherited disorder causing intense pain. Porphyrins are substances essential for haemoglobin to function. When an excess of porphyrin is present i.e. Porphyria, the cells fail to change chemicals in your body—called porphyrins and porphyrin precursors—into heme, the substance that gives blood its red colour.

According to Delveinsight, Porphyria affects 1 in 10,000 people in the 7MM. Gene therapy is observed to be fruitful as Porphyria treatment, where SIN lentiviral vector containing human ferrochelatase cDNA was driven by human ankyrin-1/β-globin HS-40 chimeric erythroid promoter/enhancer in a mice model. Ferrochelatase gene was efficiently transferred to the erythroid lineage of bone marrow and corrected all the clinical and biological alteration caused by Porphyria.

Wound Healing

A totally different field from genetic mutation and with no similarity to genodermatosis, healing of the wound is a complex mechanism with different properties and sequences of inflammation and pain. There are many underlying factors of gene therapy that aids in wound healing that include:-

  • Lack of epidermal barrier helps in easy gene transfer
  • Intervention and treatment of a limited area
  • Even gene therapy is required for a shorter amount of time, till the ulcer is healed

Gene therapy in wound healing offers valuable treatment options for non-genetic diseases treating conditions like diabetic ulcers, vascular ulcers, refractory burn wounds. It aims at enhancing the wound healing process, inhibiting post ulcer complications, e.g., scarring and keloid formation, as well as increasing the tensile strength of newly formed skin. The in-vivo approach has shown that the expression of exogenous epidermal growth factors in the skin increases wound healing by 20%. Gene-gun delivery, direct application of naked DNA, electroporative transfer, intraulcer injection, microvascular transfection, or wound bed implantation are other techniques used.

Skin Cancer

Abnormal growth of skin cells most often develops on skin exposed to the sun. But this common form of cancer can also occur on areas of your skin not ordinarily exposed to sunlight. As per DelveInsight analysis, 1 in 5 Americans is at the risk of developing skin cancer by the age of 70 and also 1-2 people die every hour in the USA due to skin cancer. It is one of the most prominent cancers in the world and surgery was considered as the only treatment for skin cancers earlier.

As gene therapy evolved, several applications of gene therapy in skin cancer treatment were proven to have a definitive impact. It includes Melanoma treatment – recently different clinical trials were undertaken using T-lymphocytes to treat melanoma. Melanoma is observed in every 3 individuals per 100,00 people in the USA. Melanoma patients were treated with genetically modified autologous lymphocytes expressing the cancer germ-line gene MAGE-A3. Increment in circulating anti-MAGE-A3 antibodies was found in 3 out of 10 patients without any toxicity or adverse effect. 

Other applications of gene therapy target on Squamous cell carcinoma treatment where replication-defective recombinant adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene (”suicide” gene) was followed by an administration of ganciclovir which was used to treat human head and neck squamous cell carcinoma successfully in a nude mice model.

Dermatology Associated Gene Therapy Companies

Some of the major biotechnological and pharmaceutical companies in Gene Therapy in Dermatology include Krystal Biotech, Castle Creek Biosciences, Almirall, Tyris Therapeutics, Abeona Therapeutics, Fibrocell Science, Amryt Pharma, Sterna Biologicals, Temprian Therapeutics, Holostem Terapie, Azitra, Novartis, Avita Medical, and several others.

Pros and Cons of Gene Therapy in the Area of Dermatology

People with rare genetic dermatological diseases include the older generation as well as younger kids, and they are well aware of their condition. The requirements, clinical trials, and outcomes are all mentioned to them and they are fully aware of the possible results. Gene therapy in dermatology only aims at improving the quality of life of the people affected. The benefits of gene therapy in the field of dermatology includes conditions that are targeted by gene therapy are typically rare, concluding a small pool of eligible patients which leads to a smaller number of study sites with a lower number of patients making it easier to research.

Efforts aimed at developing effective gene therapy for skin diseases were hampered by several key hurdles such as challenges in inducing sustained gene expression in vivo, many difficulties in targeting genes to stem cells, then researchers may require long-term safety and efficacy data, which might not be readily available, apart from that innovative treatment approaches are usually developed by small-scale biotechnological firms, but they may not have the proper resources and infrastructure required to carry out a gene therapy clinical trial.

Nonetheless, in order to build a strong value story for gene therapy in dermatology researchers can collect the data from follow-up studies, and from long-term patient surveillance, which may be required as part of the market authorization. While large pharma may have experience in dermatology, medical, operational and regulatory expertise, as well as access to physicians and markets, they might lack in innovations that are generally created by the smaller biotechs. The collaborations occurring between large pharma and biotechs give many smaller research-based companies support in the market while providing themselves access to innovation.

What Lies in the Future of Gene Therapy in Dermatology Treatment

In addition to the millions of people affected with dermatology diseases, thousands of children are born every year with autoimmune skin diseases and rare skin diseases. With continuing advances in gene therapy, one day even the formation of pathological skin lesions can be prevented, rather than treating or curing them.

Current gene therapy clinical trials are exploring the field of dermatology, most noticeably treating melanoma and healing wounds. Nowadays, genetically modified skin grafts are even used to investigate ways to treat diabetes. Many challenges can be expected to arise for biotech companies in the development of gene therapies, however, it can be safely said that this therapy option will emerge as the newest pioneer in dermatology treatment.

With continued optimization of vector design and gene transfer strategies, as well as the development of imaging tools for monitoring gene delivery and treatment response, we expect to see an increase in the number of dermatology gene therapy trials in the coming years. A few years ago, gene therapy was just considered a futuristic concept, but now is leading the dermatology research sector. With the correct guidance, expertise, aid and assistance in research, gene therapy can make path-breaking changes in the field of dermatology to cure hard to manage diseases.