Gene Therapy: Research and Treatments

What Is Gene Therapy?

Gene therapy is a new approach to treating medical conditions, which can be described as the use of genes as drugs. It works by introducing normal or therapeutic genes into people with certain disorders to overcome the effects of defective genes that may cause or play a role in the development of the condition. Gene therapy is also used to treat disorders in which the genetic cause is not known or may not be caused exclusively by genetic defects, such as Parkinson's disease and cancer.

The development of gene therapy has created a large enterprise dedicated to producing vectors, the vehicles capable of delivering therapeutic nucleic acid constructs to the appropriate target cells, organs or tissues. The development of potential gene therapies for treating many different types of diseases needs underpinning by efficient and safe transgene delivery systems.

Vectors in clinical and experimental use are either viral-derived or non-viral. Initial experimental and clinical gene therapy was based on the use of retrovirus-derived vectors, although almost any virus can be adapted as a gene therapy vector. The robustness of retroviruses is exemplified by their selection as the vectors of choice in the recent successful gene therapy clinical trial for human severe combined immunodeficiency X1 (SCID-X1) disease.

One limitation to the use of retroviruses as gene therapy vectors is their lack of integration into non-dividing cells. This failing led to the development of lentiviral vectors, which can infect both actively dividing and non-dividing cells. Other commonly used vectors are those derived from human adenoviruses, human adeno-associated viruses (AAVs) and human herpes simplex virus type 1 (HSV-1).

Each vector system has advantages and shortcomings, vis-à-vis individual gene therapy applications. To take advantage of the best features of each individual vector system, there is an intense effort to construct hybrid vector systems in which the strengths of individual vector systems are combined. An example of this is the construction of adenoviruses or HSV-1-derived vectors, which are used to deliver retroviruses and AAVs into target cells, respectively. Such chimaeric systems allow the production of vectors that can be grown to the high titres achievable with adenoviruses and have the capacity of retrovirus- or AAV-derived vectors to integrate their genomes into those of the host cell, thereby improving long-term transgene expression.

The likelihood of developing the ideal universal vector is comparable with developing the "ideal" antibiotic that treats all infectious diseases. Just as small chemical drugs each have their own niche of appropriate application, so do the viral vectors. Consequently, the aim is to develop tailored vectors that are ideal for particular applications. For example, the ideal vector for persistent, high-level gene expression in the liver will probably differ from that which is most suitable in the pituitary, brain or pancreas.

Clinical Successes of Gene Therapy

Although gene therapy is not yet used as a mainstream medical treatment, recent clinical successes predict its implementation to treat severe human clinical conditions in the near future. Recent clinical breakthroughs include:

The treatment of severe combined immunodeficiency with a retroviral vector. Cavazzana-Calvo, M. et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288, 669-672 (2000).
Hemophilia with an adeno-associated viral vector. (Kay, M.A. et al. Evidence for gene transfer and expression of factor IX in hemophilia B patients treated with an AAV vector. Nature Genet. 24, 257-261 (2000).
Cardiovascular disease with naked plasmid DNA. (Isner, J.M. & Asahara, T. Angiogenesis and vaculogenesis as therapeutic strategies for postnatal neovacularization. J. Clin. Invest. 103,1231-1266 (1999).
Cancer therapy using an oncolytic adenovirus. (Khuri, F.R. et al. A controlled trial of intratumoral ONYX-015, a selectively replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nature Med. 6, 879-885 (2000).

Our Publication Highlights

Our work has recently been portrayed in the cover of prestigious scientific journals, such as Nature Medicine, Proceedings of the National Academy of Sciences, USA and the official journal of the American Society for Gene Therapy, Molecular Therapy.

Selected Publications

Sharing What We Learn

Every day Cedars-Sinai fulfills its commitment to leading-edge healthcare by quickly instilling medical breakthroughs that have proven to create better outcomes for patients into medical practice. This ensures that patients benefit from the latest advances and have access to appropriate and innovative clinical trials and investigational studies. Cedars-Sinai is also a leader in education, sharing the knowledge gained from research and experience through residency, fellowship and teaching programs, as well as seminars, publications and community lectures.

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