There are around 6000 known genetic disorders that cause health problems with the number continuing to grow as more are discovered each year. The clinical effects can vary from just an increased risk for disease (e.g. breast cancer and BRCA1 or BRCA2 mutations) to an inevitably fatal condition (e.g. progeria). Many of the more frequently observed disorders, such as Down syndrome or Fragile X syndrome, cause severe physical and/or mental disabilities. Regardless of the symptoms, genetic disorders are caused by errors in our genome that range from single mutations in one gene to large chromosomal abnormalities (deletions, insertions, and rearrangements of our chromosomes) that affect numerous genes. Some of the known disorders are hereditary and are passed from parent to offspring, while others happen spontaneously and are not present in the parental genomes. Sadly, only 10% of these currently known genetic disorders are treatable.
Gene therapy is the medical procedure that attempts to correct genetic defects through the repair or replacement of mutant genes. Such therapies involve introducing new genetic material into the patient’s cells, a process that is not easily accomplished. The most common strategy for delivering the new genetic material is to take advantage of a microorganism already highly optimized for gene delivery, a virus. A virus consists of its own genetic material (its genome) encapsulated in a virion structure that protects the genome and delivers it into the host cell. These virions have evolved to be highly efficient structures for transporting genetic material into cells, and while we usually associate viruses with diseases they can be repurposed for therapeutic use. For gene therapy, the virion is the delivery vehicle that carries the new genetic material for correcting the patient’s gene defect. Typically, some of the viral genome is removed and replaced with the therapeutic gene material and the hybrid genome is packaged into the viral virion. These carrier viruses, often referred to as viral vectors, are also typically engineered to make them harmless if they originally had a pathogenic capability. Many different virus types have been adopted for gene therapy and the most widely used virus vectors include adenoviruses, parvoviruses, retroviruses, and herpesviruses.
A new study published in Nature Medicine uses a modified herpesvirus to treat a rare but horrific genetic disorder known as recessive dystrophic epidermolysis bullosa (RDEB). Individuals with this disorder have a defect in the gene encoding a skin protein called collagen VII. This protein is critical for forming fibers that anchor our upper skin (epidermis) to the lower skin (dermis). Without functional collagen VII, the victims of this gene defect have very fragile skin that peels, blisters, and tears apart with even simple touching. These wounds heal poorly if at all, leading to chronic pain, scarring, constant infections, and a high risk for skin cancer. In this study, a non-replicating herpesvirus was engineered to carry the wild-type collagen VII gene. Herpesviruses are ideal for this purpose as their normal target is skin cells (keratinocytes) and they infect this tissue very effectively. In cell culture and mouse models, the chimeric virus restored the production of normal collagen VII as anticipated. When applied topically in gel form onto wounds in RDEB patients in a small clinical trial, this virus therapy was effective at healing chronic wounds compared to control patients. No significant adverse effects of the treatment were observed. While this method does not cure the disorder, this topical approach could be very effective at treating and healing recalcitrant wounds in RDEB patients. This vector can be used repeatedly as needed and could greatly improve the quality of life for these individuals. Larger trials are in progress and similar positive results could see this therapy on the market in a few years.