Kordower, JH and Olanow, CW. Regulatable promoters and gene therapy for Parkinson's disease: is the only thing to fear, fear itself? Exp Neurol 209: 34-40

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Experimental Neurology (Impact Factor: 4.7). 02/2008; 209(1):34-40. DOI: 10.1016/j.expneurol.2007.08.001
Source: PubMed


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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    • "While regulated gene therapy vectors are considered to deliver a substantial safety improvement for gene therapies targeting major neurodegenerative disorders like PD,27 others discourage the use of such systems.28 A major concern is the composition of the regulation machinery, which has to be introduced into the target tissue together with the transgene of interest. "
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    ABSTRACT: Gene therapy, in its current configuration, is irreversible and does not allow control over transgene expression in case of side effects. Only few regulated vector systems are available, and none of these has reached clinical applicability yet. The mifepristone (Mfp)-regulated Gene Switch (GS) system is characterized by promising features such as being composed of mainly human components and an approved small-molecule drug as an inducer. However, it has not yet been evaluated in adeno-associated virus (AAV) vectors, neither has it been tested for applicability in viral vectors in the central nervous system (CNS). Here, we demonstrate that the GS system can be used successfully in AAV vectors in the brain, and that short-term induced glial cell line-derived neurotrophic factor (GDNF) expression prevented neurodegeneration in a rodent model of Parkinson's disease (PD). We also demonstrate repeated responsiveness to the inducer Mfp and absence of immunological tissue reactions in the rat brain. Human equivalent dosages of Mfp used in this study were lower than those used safely for treatment of psychiatric threats, indicating that the inducer could be safely applied in patients. Our results suggest that the GS system in AAV vectors is well suited for further development towards clinical applicability.Molecular Therapy-Nucleic Acids (2013) 2, e106; doi:10.1038/mtna.2013.35; published online 16 July 2013.
    Full-text · Article · Jul 2013 · Molecular Therapy - Nucleic Acids
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    • "The possibility to regulate transgene expression has been a discussed in the gene therapy field for a long time (see e.g. [1], [2]). In clinical settings, regulated transgene expression would allow for increased or decreased transgene levels in response to clinical need. "
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    ABSTRACT: Regulating transgene expression in vivo by delivering oral drugs has been a long-time goal for the gene therapy field. A novel gene regulating system based on targeted proteasomal degradation has been recently developed. The system is based on a destabilizing domain (DD) of the Escherichia coli dihydrofolate reductase (DHFR) that directs fused proteins to proteasomal destruction. Creating YFP proteins fused to destabilizing domains enabled TMP based induction of YFP expression in the brain, whereas omission of TMP resulted in loss of YFP expression. Moreover, induction of YFP expression was dose dependent and at higher TMP dosages, induced YFP reached levels comparable to expression of unregulated transgene., Transgene expression could be reversibly regulated using the DD system. Importantly, no adverse effects of TMP treatment or expression of DD-fusion proteins in the brain were observed. To show proof of concept that destabilizing domains derived from DHFR could be used with a biologically active molecule, DD were fused to GDNF, which is a potent neurotrophic factor of dopamine neurons. N-terminal placement of the DD resulted in TMP-regulated release of biologically active GDNF. Our findings suggest that TMP-regulated destabilizing domains can afford transgene regulation in the brain. The fact that GDNF could be regulated is very promising for developing future gene therapies (e.g. for Parkinson's disease) and should be further investigated.
    Full-text · Article · Sep 2012 · PLoS ONE
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    • "At present, there is relatively limited in vivo data relating to this approach, in contrast to the large number of patients who have participated in clinical trials of (noninducible) AAV-based gene therapy, for either PD or for other diseases such as Alzheimer's or Canavan disease, without any major safety concerns being raised [12, 59, 62, 100, 101]. This has led some to conclude that the continued use of better-established noninducible AAV-based gene therapies may actually be safer—based on the availability of empirical evidence available—than using novel, less well-evaluated, regulatable promoter mechanisms [102]. "
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    ABSTRACT: Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field.
    Full-text · Article · Mar 2012
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