Translating the therapeutic potential of neurotrophic factors to clinical ‘proof of concept’: A personal saga achieving a career-long quest

Bartus, Raymond T.

doi:10.1016/j.nbd.2012.04.004

Cited by 26 publications

(15 citation statements)

References 104 publications

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“…Progress achieved in the realm of gene therapy (GT) over the past decade has offered solutions to many of the delivery constraints, 5 and several aspects of PD present it overtly as an ideal clinical indication to target using GT: (i) the well-defined, localizable, and targetable neuronal systems involved with major motor symptoms, (ii) the need for relatively small titer and volume of vector targeted to those sites, which avoids the systemic circulation of immunogenic materials, and (iii) the large and increasing demand for improved therapeutics with an aging population, 4 which in whole bolsters impact and financial support for research and development. Given this rationale, PD has, for better or worse, become a key exemplar for CNS GT.…”

Section: Background: Impetus and Outcomes With Parkinson's Gene Theramentioning

confidence: 99%

“…This offers potential improvement in symptoms as well as delay in disease progression. 5,14 Both neurotrophic GT investigations to date have used AAV2 as the delivery vector; the studies diverge merely in the choice of which of two structural and functional analog proteins (neurturin (NRTN) or glia cell–derived neurotrophic factor (GDNF)) is packaged and expressed. Below we offer perspective on the outcomes of each of the PD GT clinical approaches to date.…”

Section: Parkinson's Gt Clinical Trials To Datementioning

confidence: 99%

“…5,36,41,42 The efficacy data for both phase 2 trials were mixed and disappointing, in that neither met the primary endpoint (UPDRS motor-off) within the prescribed timeframe. Notably, in the initial phase 2 trial, improvement in the primary clinical endpoint was seen beyond the prescribed assessment time ( i.e.…”

Section: Parkinson's Gt Clinical Trials To Datementioning

confidence: 99%

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Parkinson's Disease Gene Therapy: Success by Design Meets Failure by Efficacy

Bartus¹,

2014

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Over the past decade, nine gene therapy clinical trials for Parkinson's disease (PD) have been initiated and completed. Starting with considerable optimism at the initiation of each trial, none of the programs has yet borne sufficiently robust clinical efficacy or found a clear path toward regulatory approval. Despite the immediately disappointing nature of the efficacy outcomes in these trials, the clinical data garnered from the individual studies nonetheless represent tangible and significant progress for the gene therapy field. Collectively, the clinical trials demonstrate that we have overcome the major safety hurdles previously suppressing central nervous system (CNS) gene therapy, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, these studies also demonstrated controlled, highly persistent generation of biologically active proteins targeted to structures deep in the human brain. Therefore, a renewed, focused emphasis must be placed on advancing clinical efficacy by improving clinical trial design, patient selection and outcome measures, developing more predictive animal models to support clinical testing, carefully performing retrospective analyses, and most importantly moving forward—beyond our past limits.

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Section: Background: Impetus and Outcomes With Parkinson's Gene Theramentioning

confidence: 99%

Section: Parkinson's Gt Clinical Trials To Datementioning

confidence: 99%

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Parkinson's Disease Gene Therapy: Success by Design Meets Failure by Efficacy

Bartus¹,

2014

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“…Nigral expression can boost neuron survival at the level of the cell body and therefore may be complimentary to striatal administration. 12 To date, two studies have been conducted in neurotoxin rodent models comparing the neuroprotective effects of AAV neurotrophic factor ST to ST and SN delivery, both reporting increased neuroprotection of nigral neurons with SN delivery. 10,13 …”

Section: Introductionmentioning

confidence: 99%

Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways

et al. 2014

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Intrastriatal injection of recombinant adeno-associated viral vector serotype 2/1 (rAAV2/1) to overexpress the neurotrophic factor pleiotrophin (PTN) provides neuroprotection for tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc), increases THir neurite density in the striatum (ST) and reverses functional deficits in forepaw use following 6-hydroxydopamine (6-OHDA) toxic insult. Glial cell line-derived neurotrophic factor (GDNF) gene transfer studies suggest that optimal neuroprotection is dependent on the site of nigrostriatal overexpression. The present study was conducted to determine whether enhanced neuroprotection could be accomplished via simultaneous rAAV2/1 PTN injections into the ST and SN compared with ST injections alone. Rats were unilaterally injected in the ST alone or injected in both the ST and SN with rAAV2/1 expressing either PTN or control vector. Four weeks later, all rats received intrastriatal injections of 6-OHDA. Rats were euthanized 6 or 16 weeks relative to 6-OHDA injection. A novel selective total enumeration method to estimate nigral THir neuron survival was validated to maintain the accuracy of stereological assessment. Long-term nigrostriatal neuroprotection and functional benefits were only observed in rats in which rAAV2/1 PTN was injected into the ST alone. Results suggest that superior preservation of the nigrostriatal system is provided by PTN overexpression delivered to the ST and restricted to the ST and SN pars reticulata and is not improved with overexpression of PTN within SNpc neurons.

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“…5 Lyconadins A–C, members of the Lycopodium alkaloid family, were isolated by Kobayashi and co-workers from the club moss Lycopodium complanatum but in very low yield. 6 Both lyconadins A and B have been shown to promote the biosynthesis of nerve growth factors (NGF), 7 which are essential for maintaining neuronal balances. So far, their mechanisms of action remain unknown.…”

mentioning

confidence: 99%