Contributor: Keith A. Goldan, WG’02
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Few fields of science have sparked more hope and promise than gene therapy. A powerfully simple concept, gene therapy targets the genetic source of disease. Using a vector such as a virus (including AAV, adenovirus, and lentivirus) as a vehicle to transport a normal gene into the body, we’re able to replace missing or defective genes that are causing disease. Gene therapy is particularly well-suited for treating genetic diseases and disorders with unmet medical needs, such as Leber congenital amaurosis, a rare form of blindness; lipoprotein lipase deficiency, a rare inherited disorder that can cause severe pancreatitis; and recessive dystrophic epidermolysis bullosa, or RDEB, a congenital orphan skin disease that often leads to death.
While there are not yet any FDA-approved genetic therapies available in the U.S., researchers and clinicians have experienced success with gene therapy. In fact, the University of Pennsylvania has made significant contributions to the evolution of gene therapy, including conducting many of the seminal studies.
Addressing Challenges
Not unlike other evolving technologies, gene therapy has its issues — both historical and current. One of its most difficult challenges has been and continues to be determining the appropriate viral vector to deliver a normal gene to cells without compromising the patient’s immune system. Unfortunately, there have been harmful consequences. Patient deaths were reported in separate clinical trials in the late 1990’s and early 2000’s which led a number of gene therapy companies to fold and made financing new gene therapy companies almost impossible.
More recently, researchers have improved and optimized viral vector technologies — specifically, designing less immunogenic vectors that potentially will not trigger harmful immune responses. In addition, several other positive factors have contributed to gene therapy’s progress, including greater involvement of government regulators for pharmaceuticals (e.g., U.S. Food and Drug Administration), ongoing academic research, and greater collaboration between academic institutions and industry.
Advancing the Technology
Overall, the impact of gene therapy has been remarkable. Eyesight has been restored with a gene therapy for patients with Leber congenital amaurosis, a rare form of blindness. The first gene therapy trial in patients with this eye disease was conducted by the University of Pennsylvania and Children’s Hospital of Philadelphia and was published in 2008.1
Another major milestone occurred in 2012 when the EU approved the first gene therapy for commercial use in the Western world. This medication — trade named Glybera — was designed to treat a rare disorder called lipoprotein lipase deficiency in which patients have extremely high blood-fat levels and suffer from recurring bouts of painful pancreatitis. In further developments, gene therapy studies have shown unprecedented results in patients suffering from blood cancers. In therapeutics for cancer, one gene therapy has an expanded indication to activate the immune system against a disease, in addition to its initial gene therapy indication to correct a defective gene.
Moreover, within the past 18 months, gene therapy has surged in the U.S. due to an advanced clinical development pipeline, and an increase in the number of emerging biotech companies focused on gene therapy. Important, too, are that investments in the field have totaled nearly $6 billion in this same timeframe.2
Offering Hope for Patients with a Devastating Rare Skin Disease
Gene therapy has the extraordinary potential to positively impact the biotechnology industry and offer hope to patients living with rare genetic diseases who have few, if any, treatment options. Fibrocell Science, an autologous cell and gene therapy company based in Exton, PA, is focusing its drug development efforts on rare skin and connective tissue diseases with high unmet medical needs. The company’s lead gene therapy program is devoted to an orphan skin disease known as recessive dystrophic epidermolysis bullosa, or RDEB—a congenital, progressive, devastatingly painful and debilitating genetic disease that appears at birth and often leads to death before a patient’s 30th birthday.3 RDEB is caused by a mutation of the COL7A1 gene resulting in the absence or deficiency of a vital protein known as type VII collagen (COL7). COL7 forms anchoring fibrils that hold together the layers of skin. Without these fibrils, skin layers easily separate causing severe blistering, open wounds and scarring in response to any kind of friction, including normal daily activities like rubbing or scratching. Children who inherit the condition are often called “butterfly children” because their skin is as fragile as a butterfly’s wings. There are approximately 1,100 – 2,500 RDEB patients in the U.S.,4 and today they are limited to symptomatic treatments, including daily bandaging, hydrogel dressings, antibiotics, feeding tubes, and surgeries.
FCX-007, Fibrocell’s orphan gene therapy product candidate for the treatment RDEB, is an autologous fibroblast transduced with a lentiviral vector that encodes COL7 and is being developed in collaboration with Intrexon. By genetically modifying autologous fibroblasts, ex vivo, to produce COL7, culturing them and then treating blisters and wounds locally via injection, FCX-007 offers the potential to address the underlying cause of RDEB by providing high levels of COL7 (the missing/deficient protein) directly to the affected areas to keep the wounds closed. Fibrocell chose the lentiviral vector because it can integrate its DNA into the fibroblast so that the genetic modification — in this case, the production of COL7 — is passed on to the progeny cells. With this approach, Fibrocell’s hope is to begin treating RDEB children at a very early age to reduce their pain and suffering and dramatically improve the quality of their lives and that of their families.
Contact Keith at: [email protected]
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References:
- Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 2008;19:979-90.
- Martz, L. Gene Therapy’s Coming of Age. BioCentury. 23 July 2015. Available (with subscription) at: http://www.biocentury.com/innovations/coverstory/2015-07-23/why-gene-therapy-is-hot-after-more-than-20-years-of-research-s01. Accessed October 2, 2015.
- Fine JD, Bauer E, McGuire J, and Moshell, A. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances and the Findings of the National Epidermolysis Bullosa Registry. © The Johns Hopkins University Press, Baltimore and London, 1999.
- Petrof G., et al. Fibroblast cell therapy enhances initial healing in recessive dystrophic epidermolysis bullosa wounds: results of a randomized, vehicle-controlled trial. Brit J Dermatol. 2013 Nov;169(5):1025-33.