Optimizing Transgene Configuration and Protein Fusions to Maximize Dopamine Production for the Gene Therapy of Parkinson's Disease

Stewart, Harry E.; Ralph, G; Fong-Wong, Liang; Strickland, Iain T.; McCloskey, Laura J.; Barnes, L; Blount, Ian; Wells, Owen; Truran, Christelle J M; Kingsman, Alan J.; Palfi, Stéphane; Mitrophanous, Kyriacos

doi:10.1089/humc.2016.056

Cited by 19 publications

(28 citation statements)

References 26 publications

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“…Therefore, a new vector (OXB-102) has been recently developed in which the configuration of three dopamine biosynthesis enzymes was further optimized to increase the capacity for dopamine production significantly compared to ProSavin. 20 This vector is under preclinical development and, pending regulatory approval, will be assessed in a new Phase I/II study to determine the appropriate dose before a larger placebo-controlled Phase IIb clinical trial is undertaken.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Follow-Up of a Phase I/II Study of ProSavin, a Lentiviral Vector Gene Therapy for Parkinson's Disease

Palfi

Gurruchaga

Lepetit

et al. 2018

Human Gene Therapy Clinical Development

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102

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Parkinson's disease is typically treated with oral dopamine replacement therapies. However, long-term use is complicated by motor fluctuations from intermittent stimulation of dopamine receptors and off-target effects. ProSavin, a lentiviral vector based gene therapy that delivers local and continuous dopamine, was previously shown to be well tolerated in a Phase I/II first-in-human study, with significant improvements in motor behavior from baseline at 1 year. Here, patients with Parkinson's disease from the open-label trial were followed up in the long term to assess the safety and efficacy of ProSavin after bilateral injection into the putamen. Fifteen patients who were previously treated with ProSavin have been followed for up to 5 years, with some having been seen for 8 years. Eight patients received deep brain stimulation at different time points, and their subsequent assessments continued to assess safety. Ninety-six drug-related adverse events were reported (87 mild, 6 moderate, 3 severe) of which more than half occurred in the first year. The most common drug-related events were dyskinesias (33 events, 11 patients) and on–off phenomena (22 events, 11 patients). A significant improvement in the defined “off” Unified Parkinson's Disease Rating Scale part III motor scores, compared to baseline, was seen at 2 years (mean score 29 · 2 vs. 38 · 4, n = 14, p < 0.05) and at 4 years in 8/15 patients. ProSavin continued to be safe and well tolerated in patients with Parkinson's disease. Moderate improvements in motor behavior over baseline continued to be reported in the majority of patients who could still be evaluated up to 5 years of follow-up.

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Section: Discussionmentioning

confidence: 99%

Long-Term Follow-Up of a Phase I/II Study of ProSavin, a Lentiviral Vector Gene Therapy for Parkinson's Disease

Palfi

Gurruchaga

Lepetit

et al. 2018

Human Gene Therapy Clinical Development

Self Cite

102

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“…The lentiviral-based drug is injected into the patients’ striatum, in order to reprogram transduced cells to secrete DA. The treatment, although encouraging, showed only little efficacy and the trial is at the moment under examination, waiting for optimal mode and dose of delivery [ 197 , 198 ].…”

Section: Development Of Mirna-based Therapies For Pd Treatmentmentioning

confidence: 99%

microRNAs in Parkinson’s Disease: From Pathogenesis to Novel Diagnostic and Therapeutic Approaches

Leggio

Vivarelli

L’Episcopo

et al. 2017

IJMS

187

136

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Parkinson’s disease (PD) is the most prevalent central nervous system (CNS) movement disorder and the second most common neurodegenerative disease overall. PD is characterized by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) within the midbrain, accumulation of alpha-synuclein (α-SYN) in Lewy bodies and neurites and excessive neuroinflammation. The neurodegenerative processes typically begin decades before the appearance of clinical symptoms. Therefore, the diagnosis is achievable only when the majority of the relevant DAergic neurons have already died and for that reason available treatments are only palliative at best. The causes and mechanism(s) of this devastating disease are ill-defined but complex interactions between genetic susceptibility and environmental factors are considered major contributors to the etiology of PD. In addition to the role of classical gene mutations in PD, the importance of regulatory elements modulating gene expression has been increasingly recognized. One example is the critical role played by microRNAs (miRNAs) in the development and homeostasis of distinct populations of neurons within the CNS and, in particular, in the context of PD. Recent reports demonstrate how distinct miRNAs are involved in the regulation of PD genes, whereas profiling approaches are unveiling variations in the abundance of certain miRNAs possibly relevant either to the onset or to the progression of the disease. In this review, we provide an overview of the miRNAs recently found to be implicated in PD etiology, with particular focus on their potential relevance as PD biomarkers, as well as their possible use in PD targeted therapy.

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“…Vectors derived from human immunodeficiency virus 1 and 2 (HIV-1- and HIV-2) together with those derived from simian immunodeficiency virus (SIV), equine immune anaemia virus (EIAV), or adeno-associated virus are among the most intensively studied systems used for gene transfer into neuronal cells (Mitrophanous et al 1999 ; D´Costa et al 2003 ; Liehl et al 2007 ; Trabalza et al 2013 ; Hocquemiller et al 2016 ; Stewart et al 2016 ). Data from the first clinical trials (phase 1 or 1/2) utilising adeno-associated and lentiviral vectors for therapy of brain diseases are available (Mittermeyer et al 2012 ; Palfi et al 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…So far, published in vivo studies on brain cell transduction after injection of transgenic lentiviruses concentrate mostly on single cell populations in defined regions of interest, such as corpus striatum and substantia nigra (Naldini et al 1996a ; Blömer et al 1997 ; Bensadoun et al 2000 ; Stewart et al 2016 ), hippocampus (Naldini et al 1996a ; Blömer et al 1997 ), or selected nuclei (Sinnayah et al 2002 ). The possibility of external regulation of the transcription of lentiviral vectors incorporated into the genome of cerebral neurons in vivo has been shown, e.g., by Haack et al ( 2004 ) and Vogel et al ( 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Tropism, intracerebral distribution, and transduction efficiency of HIV- and SIV-based lentiviral vectors after injection into the mouse brain: a qualitative and quantitative in vivo study

Hlavatý

Tonar

Renner

et al. 2017

Histochem Cell Biol

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Lentiviruses are suitable to transfer potential therapeutic genes into non-replicating cells such as neurons, but systematic in vivo studies on transduction of neural cells within the complete brain are missing. We analysed the distribution of transduced cells with respect to brain structure, virus tropism, numbers of transduced neurons per brain, and influence of the Vpx or Vpr accessory proteins after injection of vectors based on SIVsmmPBj, HIV-2, and HIV-1 lentiviruses into the right striatum of the mouse brain. Transduced cells were found ipsilaterally around the injection canal, in corpus striatum and along corpus callosum, irrespective of the vector type. All vectors except HIV-2SEW transduced also single cells in the olfactory bulb, hippocampus, and cerebellum. Vector HIV-2SEW was the most neuron specific. However, vectors PBjSEW and HIV-1SEW transduced more neurons per brain (means 41,299 and 32,309) than HIV-2SEW (16,102). In the presence of Vpx/Vpr proteins, HIV-2SEW(Vpx) and HIV-1SEW(Vpr) showed higher overall transduction efficiencies (30,696 and 27,947 neurons per brain) than PBjSEW(Vpx) (6636). The distances of transduced cells from the injection canal did not differ among the viruses but correlated positively with the numbers of transduced neurons. The presence of Vpx/Vpr did not increase the numbers of transduced neurons. Parental virus type and the vector equipment seem to influence cellular tropism and transduction efficiency. Thus, precision of injection and choice of virus pseudotype are not sufficient when targeted lentiviral vector transduction of a defined brain cell population is required.Electronic supplementary materialThe online version of this article (doi:10.1007/s00418-017-1569-1) contains supplementary material, which is available to authorized users.

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Optimizing Transgene Configuration and Protein Fusions to Maximize Dopamine Production for the Gene Therapy of Parkinson's Disease

Cited by 19 publications

References 26 publications

Long-Term Follow-Up of a Phase I/II Study of ProSavin, a Lentiviral Vector Gene Therapy for Parkinson's Disease

Long-Term Follow-Up of a Phase I/II Study of ProSavin, a Lentiviral Vector Gene Therapy for Parkinson's Disease

microRNAs in Parkinson’s Disease: From Pathogenesis to Novel Diagnostic and Therapeutic Approaches

Tropism, intracerebral distribution, and transduction efficiency of HIV- and SIV-based lentiviral vectors after injection into the mouse brain: a qualitative and quantitative in vivo study

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