Regulatable promoters and gene therapy for Parkinson's disease: Is the only thing to fear, fear itself?
ABSTRACT Gene therapy for Parkinson's disease has become a clinical reality with three different approaches currently being tested in patients. All three trials employ an adeno-associated virus with a type two serotype (AAV2). To date, no serious adverse events related to the injections of therapeutic vectors have been reported in any patient. This safety profile was predicted based upon, in some cases, exhaustive preclinical testing in both rodent and primate species. Still some argue that regulatable promoters are required so that expression of the transgene can be halted should untoward side effects arise. We argue that given the current empirical data base of AAV2, the lack of regulatable promoters that have been proven to be safe and effective, and the pressing clinical needs of PD patients, the mandatory use of regulatable vectors is not only unnecessary but, in some instances, misguided and potentially dangerous. This commentary will outline the issues related to the use of regulatable promoters for gene therapy for PD and express our opinion as to why mandating the use of such promoters might result in outcomes that are unsafe, unproductive, and counter to the progress of scientifically sound, clinical research.
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ABSTRACT: It is well-known that the variations of Goos–Hänchen shifts (GHSs) are closely associated with the energy flux provided by evanescent states in the case of total internal reflection. However, when the frustrated total internal reflection (FTIR) is realized with double-prism system operated in the microwave frequency, we observe that the GHSs for the reflected beam show periodic, resembling the phenomenon for transmitted beams reported in the literatures, versus either the operating frequency or the air layer thickness, which is different from the variation of the corresponding reflected energy. Moreover, in another FTIR based system fabricated by a composite absorptive material slab with a two-dimensional top layer of frequency selective surface (FSS), the GHSs for reflected beam are discovered as not only resonant but also negative with the incidence of transverse electric that is TE polarized, just as predicted theoretically in the literatures.Optics Communications 05/2011; 284(10):2604-2607. DOI:10.1016/j.optcom.2011.01.038 · 1.54 Impact Factor
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ABSTRACT: Neurotrophic factors have raised hopes to be able to cure symptoms and to prevent progressive neurodegeneration in devastating neurological diseases. Gene therapy by means of viral vectors can overcome the hurdle of targeted delivery, but in its current configuration is irreversible and thus much less controllable than classical pharmacotherapies. We thus aimed at developing a strategy allowing for both, curative and controllable neurotrophic factor expression. Therefore, the short-term, intermittent and reversible expression of a neutrophic factor was evaluated for therapeutic efficacy in a slowly progressive animal model of Parkinson´s disease (PD). We demonstrate that short-term induced expression of glial cell line derived neurotrophic factor (GDNF) is sufficient to provide i) substantial protection of nigral dopaminergic neurons from degeneration and ii) restoration of dopamine supply and motor behaviour in the partial striatal 6-OHDA model PD. These neurorestorative effects of GDNF lasted several weeks beyond the time of its expression. Later on, therapeutic efficacy ceased, but was restored by a second short induction of GDNF expression, demonstrating that monthly application of the inducing drug mifepristone was sufficient to maintain neuroprotective and neurorestorative GDNF levels. These findings suggest that forthcoming gene therapies for PD or other neurodegenerative disorders can be designed in a way that low frequency application of an approved drug can provide controllable and therapeutically efficient levels of GDNF or other neurotrophic factors. Neurotrophic factor expression can be withdrawn in case of off-target effects or sufficient clinical benefit, a feature that may eventually increase acceptance of gene therapy for less advanced patients, which may profit better from such approaches.Neurobiology of Disease 01/2014; 65. DOI:10.1016/j.nbd.2014.01.009 · 5.20 Impact Factor
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ABSTRACT: The pharmaceutical industry's development of therapeutic medications for the treatment of Parkinson's disease (PD) endures, as a result of the continuing need for better agents, and the increased clinical demand due to the aging population. Each new drug offers advantages and disadvantages to patients when compared to other medical offerings or surgical options. Deep brain stimulation (DBS) has become a standard surgical remedy for the effective treatment of select patients with PD, for whom most drug regimens have failed or become refractory. Similar to DBS as a surgical option, gene therapy for the treatment of PD is evolving as a future option. In the four different PD gene therapy approaches that have reached clinical trials investigators have documented an excellent safety profile associated with the stereotactic delivery, viral vectors and doses utilized, and transgenes expressed. In this article, we review the clinically relevant gene therapy strategies for the treatment of PD, concentrating on the published preclinical and clinical results, and the likely mechanisms involved. Based on these presentations, we advance an analysis of how the nature of the gene therapy used may eventually expand the scope and utility for the management of PD.Pharmaceuticals 12/2012; 5(6):553-590. DOI:10.3390/ph5060553