A Stable Producer Cell Line for the Manufacture of a Lentiviral Vector for Gene Therapy of Parkinson's Disease

Stewart, Harry E.; Fong-Wong, Liang; Strickland, Iain T.; Chipchase, Daniel; Kelleher, Michelle; Stevenson, Leanne; Thoree, Vinay; McCarthy, Janine; Ralph, G; Mitrophanous, Kyriacos; Radcliffe, Pippa A

doi:10.1089/hum.2010.142

Cited by 32 publications

(18 citation statements)

References 35 publications

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“…In an attempt to improve dopamine production in the striatum, intrastriatal injections of a tricistronic lentivirus encoding for tyrosine hydroxylase, aromatic amino acid decarboxylase and GTP cyclohydrolase were investigated ((Jarrya et al 2009; Stewart et al 2009; Grosset 2010; Stewart et al 2011) and reviewed in (Carlsson et al 2007; Feng and Maguire-Zeiss 2010)). A dose dependent effect has been identified with the most robust motor benefits noted to date of 43 % at six months postinjection.…”

Section: 6 Treatmentmentioning

confidence: 99%

Parkinson’s Disease

Mhyre¹,

Boyd²,

Hamill³

et al. 2012

Subcellular Biochemistry

331

203

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Parkinson’s disease (PD) is the most common age-related motoric neurodegenerative disease initially described in the 1800’s by James Parkinson as the ‘Shaking Palsy’. Loss of the neurotransmitter dopamine was recognized as underlying the pathophysiology of the motor dysfunction; subsequently discovery of dopamine replacement therapies brought substantial symptomatic benefit to PD patients. However, these therapies do not fully treat the clinical syndrome nor do they alter the natural history of this disorder motivating clinicians and researchers to further investigate the clinical phenotype, pathophysiology/pathobiology and etiology of this devastating disease. Although the exact cause of sporadic PD remains enigmatic studies of familial and rare toxicant forms of this disorder have laid the foundation for genome wide explorations and environmental studies. The combination of methodical clinical evaluation, systematic pathological studies and detailed genetic analyses have revealed that PD is a multifaceted disorder with a wide-range of clinical symptoms and pathology that include regions outside the dopamine system. One common thread in PD is the presence of intracytoplasmic inclusions that contain the protein, α-synuclein. The presence of toxic aggregated forms of α-synuclein (e.g., amyloid structures) are purported to be a harbinger of subsequent pathology. In fact, PD is both a cerebral amyloid disease and the most common synucleinopathy, that is, diseases that display accumulations of α-synuclein. Here we present our current understanding of PD etiology, pathology, clinical symptoms and therapeutic approaches with an emphasis on misfolded α-synuclein.

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Section: 6 Treatmentmentioning

confidence: 99%

Parkinson’s Disease

Mhyre¹,

Boyd²,

Hamill³

et al. 2012

Subcellular Biochemistry

331

203

View full text Add to dashboard Cite

show abstract

“…Another clinical trial utilized lentiviral vectors for delivery of multiple genes involved in dopamine biosynthesis. This vector (ProSavin) is currently being tested in Phase I/II trials for PD (Grosset, 2010; Stewart et al, 2011). Finally, two more recent trials utilized lentiviral vectors for gene therapy of inherited diseases; metachromatic leukodystrophy (MLD) (Biffi et al, 2013) (Phase I/II), and Wiskott–Aldrich syndrome (WAS) (Aiuti et al, 2013) (Phase I/II) are discussed in this chapter.…”

Section: Cns Clinical Trials Utilizing Retroviral Vectorsmentioning

confidence: 99%

Clinical Applications Involving CNS Gene Transfer

Kantor

McCown

Leone

et al. 2014

Advances in Genetics

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Diseases of the central nervous system (CNS) have traditionally been the most difficult to treat by traditional pharmacological methods, due mostly to the blood–brain barrier and the difficulties associated with repeated drug administration targeting the CNS. Viral vector gene transfer represents a way to permanently provide a therapeutic protein within the nervous system after a single administration, whether this be a gene replacement strategy for an inherited disorder or a disease-modifying protein for a disease such as Parkinson's. Gene therapy approaches for CNS disorders has evolved considerably over the last two decades. Although a breakthrough treatment has remained elusive, current strategies are now considerably safer and potentially much more effective. This chapter will explore the past, current, and future status of CNS gene therapy, focusing on clinical trials utilizing adeno-associated virus and lentiviral vectors.

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“…Only one of the reported inducible HIV-based PCLs, named GPRG, has been proposed for the production of therapeutic vectors for use in clinical trials targeting SCID-Xl1617. Another inducible EIAV-based LV producer cell line has been developed to make therapeutic vectors for use in clinical trials targeting Parkinson's disease1819. However, the scaling-up of inducible systems necessary for clinical-grade LV production is problematic, and additional purification steps of the vector preps to eliminate inducing agents are required.…”

mentioning

confidence: 99%

Construction of stable packaging cell lines for clinical lentiviral vector production

Sanber

Knight

Stephen

et al. 2015

Sci Rep

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Lentiviral vectors are useful experimental tools for stable gene delivery and have been used to treat human inherited genetic disorders and hematologic malignancies with promising results. Because some of the lentiviral vector components are cytotoxic, transient plasmid transfection has been used to produce the large batches needed for clinical trials. However, this method is costly, poorly reproducible and hard to scale up. Here we describe a general method for construction of stable packaging cell lines that continuously produce lentiviral vectors. This uses Cre recombinase-mediated cassette exchange to insert a codon-optimised HIV-1 Gag-Pol expression construct in a continuously expressed locus in 293FT cells. Subsequently Rev, envelope and vector genome expression cassettes are serially transfected. Vector titers in excess of 106 transducing units/ml can be harvested from the final producer clones, which can be increased to 108 TU/ml by concentration. This method will be of use to all basic and clinical investigators who wish to produce large batches of lentiviral vectors.

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A Stable Producer Cell Line for the Manufacture of a Lentiviral Vector for Gene Therapy of Parkinson's Disease

Cited by 32 publications

References 35 publications

Parkinson’s Disease

Parkinson’s Disease

Clinical Applications Involving CNS Gene Transfer

Construction of stable packaging cell lines for clinical lentiviral vector production

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