By Clinical Informatics News Staff

December 27, 2013 | Gene therapy continues to move in fits and lurches toward commercialization, with major setbacks trailing the technology even as clinical trials spark hopes that therapeutic DNA might soon be used to fight Parkinson’s disease, hemophilia, SCID, and dozens of other tenacious conditions. 2013 was expected to be a landmark year for gene therapy, after a November 2012 decision by the European Commission made Glybera the first such therapy approved for sale in the Western world. A treatment for the orphan genetic disease lipoprotein lipase deficiency (LPLD), which shuts down the body’s ability to digest fat, Glybera was scheduled to reach the market in the summer of 2013. However, its manufacturer, UniQuire, has still not released the drug as the year draws to a close, nor has the FDA followed its European counterpart’s lead by approving the therapy in the United States.

The clinical trials that led to Glybera’s approval followed patients for only one to two years after treatment. The drug was found to be safe and effective over this period, a significant victory for an industry that just a decade earlier was still reeling from the death of Jesse Gelsinger, who suffered a fatal immune reaction to gene therapy for a rare metabolic disorder in 1999, and a case in 2002 in which infants suffering from SCID developed leukemia after a round of gene therapy inserted DNA into a sensitive region of the genome.

Gene therapy has grown much safer in the years since, but many trials have still had difficulty sustaining efficacy over a period of months or years, requiring repeated doses of their DNA vectors. UniQuire contends that a single course of the fabulously expensive Glybera – estimated at over $1.5 million, the therapy has been called “the most expensive drug in the world” – will be enough to treat LPLD for a lifetime. As UniQuire and other hopeful gene therapy companies seek to deliver permanent cures, it is crucial to understand how this very young technology holds up in the long term.

Yesterday, a paper published in Stem Cell Reports, an open access division of Cell, addressed the progress of a man who underwent a clinical gene therapy trial in 2006 for a rare and painful skin condition. This is one of the longest-term follow-ups yet reported for a single course of gene therapy. The researchers come from the University of Modena and Reggio Emilia, in Italy, where the clinical trial was originally conducted. The patient, who has a mutation to the LAMB3 gene causing epidermolysis bullosa, suffers from severe blisters that develop under even the smallest amount of friction.

In the 2006 trial, researchers took biopsies from the patient’s palm to obtain epidermal stem cells. These cells were treated with a retrovirus that inserted a normal copy of the LAMB3 gene, and were then surgically grafted to areas of the patient’s upper thighs.

Six and a half years later, the follow-up showed that the treated area had been effectively healed: the upper thighs had no blisters, even in one area that had been badly bruised in the period after treatment, which in epidermolysis bullosa would normally result in extreme blistering. Biopsies revealed that all skin cells in the treated areas were palm stem cells carrying the modified “normal” gene. Meanwhile, other areas of the patient’s skin remained affected by the disease. The patient had experienced no negative side effects from treatment. “These findings pave the way for the future safe use of epidermal stem cells for combined cell and gene therapy of epidermolysis bullosa and other genetic skin diseases,” said senior author Michele De Luca in a statement.

The results are especially significant because of the cellular target of the therapy. Keratinocytes, the skin cells of the outer, epidermal layer, are among the most rapidly replaced cells in the human body, turning over every one to two months. The researchers estimate that their patient had completely renewed his transplanted cells at least eighty times leading up to the follow-up study, meaning the treated area retained its unique genetic makeup for dozens of generations. While grafting of transgenic stem cells is an unusual case of gene therapy, the procedure’s lasting benefits, after just a single treatment, are a hopeful sign that treated DNA can be a long-term solution for chronic conditions.

Although the path to routine use of gene therapy has been unsteady, the next few years are likely to see not only the first commercial treatments in both Europe and the U.S., but also an outpouring of innovation as a regulatory path for the technology becomes established. Today, we are at a point where gene therapy has been a part of the experimental environment long enough to begin viewing these treatments over a period of years rather than months. Studies like the one published yesterday will have to be scrutinized carefully as developers and regulators gauge the safety and promise of these new therapies over the course of patients’ lifetimes.