Gene Therapy Clinical Trials in the Human Brain

Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10021, USA.
Frontiers of neurology and neuroscience 02/2009; 25:180-8. DOI: 10.1159/000209498
Source: PubMed


The longstanding promise of gene therapy of all types has yet to be fully realized. After a difficult period, however, developments in recent years have created a resurgence of interest in the clinical utility of this unique technology. To the casual observer, the number of studies in the brain which have entered clinical trials is often surprising. The excellent safety record of the numerous studies outlined above and several others not reviewed here, combined with encouraging preliminary efficacy data suggests that gene therapy will continue to evolve as a therapeutic option in clinical trials for CNS disease. With the explosion in human trials for these disorders, it is very possible that the next few years will finally see sufficient success in advanced trials of one or more approaches to justify FDA approval and use in general clinical practice.

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    • "In summary, gene therapy for psychiatric disorders has not yet reached the point of translating findings in animal models to the human sphere. However, it is important to note that CNS gene therapy is already undergoing clinical trials, for example in patients with malignant brain tumours (Barzon et al. 2006; Kaplitt 2009). Should gene therapy prove to be useful and safe in severe and life-threatening neurological conditions, its use in psychiatry might come sooner than presently imagined. "
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    ABSTRACT: There is no indication that gene therapy can be applied in psychiatric patients any time soon. However, there are several promising developments on the level of experimental neuroscience indicating that gene therapy approaches have an effect in animal models of several psychiatric disorders including drug addiction, affective disorders, psychoses and dementia, modifying behavioural parameters via interventions on the molecular and cellular level. However, before gene therapy in psychiatric disorders can be considered on the human level, not only neurobiological and technical problems need to be overcome, but also important ethical questions answered.
    The World Journal of Biological Psychiatry 09/2011; 12 Suppl 1(S1):16-8. DOI:10.3109/15622975.2011.601927 · 4.18 Impact Factor
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    ABSTRACT: The advent of viral gene therapy technology has contributed greatly to the study of a variety of medical conditions, and there is increasing promise for clinical translation of gene therapy into human treatments. Adeno-associated viral (AAV) vectors provide one of the more promising approaches to gene delivery, and have been used extensively over the last 20 years. Derived from nonpathogenic parvoviruses, these vectors allow for stable and robust expression of desired transgenes in vitro and in vivo. AAV vectors efficiently and stably transduce neurons, with some strains targeting neurons exclusively in the brain. Thus, AAV vectors are particularly useful for neurodegenerative diseases, which have led to numerous preclinical studies and several human trials of gene therapy in patients with Parkinson's disease, Alzheimer's disease, and pediatric neurogenetic disorders. Here, we describe an efficient and reliable method for the production and purification of AAV serotype 2 vectors for both in vitro and in vivo applications.
    Methods in molecular biology (Clifton, N.J.) 01/2011; 793:443-55. DOI:10.1007/978-1-61779-328-8_29 · 1.29 Impact Factor
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    ABSTRACT: A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase-treated mice, both at 1-year and at 2-year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof-of-principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase-based treatment, and demonstrate the feasibility of anti-aging gene therapy. See accompanying article
    EMBO Molecular Medicine 08/2012; 4(8):691-704. DOI:10.1002/emmm.201200245 · 8.67 Impact Factor
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