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Progress with a new gene therapy in severe skin disease

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Progress with a new gene therapy in severe skin disease

22 December, 2022

A serious skin disease that causes large painful blisters may finally be close to a medical solution. A new gene therapy developed by Stanford Medicine, administered on the skin as a gel, has shown remarkably positive phase III results for the treatment of wounds that have remained unhealed for several years. An FDA approval could come as early as Q1 2023.

Patients suffering from the skin disease epidermolysis bullosa (EB) often have large open wounds that in some cases do not heal for several years. Today, there are no curative treatments for the disease and the intense pains that the disease causes are therefore only treated with symptom-relieving methods. Sufferers are vulnerable to infections and skin cancer, and they often die in early adulthood.

The disease includes about 20 different subcategories that are characterised by a hereditary propensity for blisters on the skin. The three most common are EB simplex, junctional EB and dystrophic EB, while the most severe form, Herlitz, affects children in infancy and is fatal due to the high risk of infection.

The background of the disease

The skin is made up of several layers where the outermost layer, the epidermis, consists of cells (keratinocytes), that is constantly replaced by new cells. In healthy skin, these cells attach to each other using microscopic protein threads but if this process does not function as it should, it gradually leads to fluid-filled blisters and potentially to one of the different forms of epidermolysis bullosa. The reason for this is a genetic mutation that involves an inability to produce a specific collagen protein, type VII (C7).

Wound healing in 3 out of 4 patients

The drug candidate B-VEC, a gene therapy in the form of a gel applied to patients’ wounds, has been developed by researchers at Stanford University School of Medicine, while the Pittsburgh-based pharmaceutical company Krystal Biotech, has tested and developed the gel for clinical use.

A smaller study in nine patients conducted earlier this year at Stanford was the first to show that gene therapy vectors for skin diseases can be effective when applied topically as a gel. In addition, the current study was the first clinical study of a gene therapy for the treatment of children and younger adults suffering from epidermolysis bullosa.

This week, a larger follow-up clinical study with 31 patients showed improved wound healing in those who received active treatment. Sixty-seven per cent of the wounds treated with the gel, which is applied to the skin during bandage changes, healed completely after six months of weekly treatment, compared to 22 per cent with placebo. According to the researchers, one of the patients experienced a life-changing improvement and a great difference in quality of life with the pain completely disappearing.

A current limitation of the treatment is that the effects of the gel are not permanent and many of the patients have experienced reappearance of some wounds. However, given that no side effects have been seen with repeated treatment, it is possible that repeated treatments may be effective for long periods of time. However, the fact that the wounds in some cases reappeared did not surprise the researchers who will probably try to produce an updated version of the treatment.

A modified herpes simplex virus

The B-VEC treatment has been developed to deliver a copy of the collagen VII gene to the skin’s surface, which then manufactures the missing protein and stabilises the skin’s structure. Because the herpes virus has evolved to evade the human immune system, the gel can be applied repeatedly without triggering an immune response that has hindered previous gene therapies that use other viruses to deliver corrective genes to the body.

The researchers now hope that the results with the modified herpes virus will ultimately lead to more gene therapy treatments for other diseases where genes are missing or damaged. These hopes are justified as several skin diseases are caused by single gene mutations and could hypothetically be treated with this technique.

Progress of gene therapies in 2022

The success of B-VEC is far from the only example pointing to the increased importance of gene therapies in 2022. For example, CSL Behring’s hemophilia B gene therapy Hemgenix has received FDA approval. With a price tag of USD 3.5 million per dose, Hemgenix is now the most expensive drug in the world. PTC Therapeutics has received market approval from the European Commission for the gene therapy Upstaza for the treatment of a rare genetic disease. The same authority has also approved BioMarin’s gene therapy for the treatment of hemophilia A, Roctavian. In addition, the FDA has approved two of Bluebird bio’s gene therapy treatments, Zynteglo and Skysona.

In Sweden, there is only one listed company that develops gene therapies, namely CombiGene. CG01 is being developed for the treatment of drug-resistant epilepsy and CGT2 for the treatment of lipodystrophy. Last year, CombiGene signed an exclusive collaboration and licensing agreement worth up to USD 328.5 million with US-based Spark Therapeutics for the development of CG01. The project is now in the final phase of the preclinical development, with the hope of being able to start the first study in humans under the leadership of Spark.

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