Long-Term Safety of GDNF Gene Delivery in the Retina

Wu, Wei; Lai, Chao‐Lun; Chen, Show Li; Sun, Ming; Xiao, Xiao; Chen, Tun Lu; Lin, Ken Kuo; Kuo, Shi‐Wen; Tsao, Yeou‐Ping

doi:10.1080/02713680591005922

Cited by 10 publications

(5 citation statements)

References 44 publications

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“…Following the concerns regarding the suppression of retinal function caused by CNTF, it has been demonstrated that AAV-mediated GDNF expression does not result in a reduction in normal retinal function; wild-type mice treated in one eye with highdose AAV.GDNF show no reduction in ERG b-wave amplitudes or waveform when compared with untreated eyes . This result confirms the findings of a previous study in rats, where long-term safety of AAVmediated GDNF expression was demonstrated by histology and electroretinography [Wu et al, 2005]. These studies demonstrate the potential of GDNF as a neuroprotective agent for retinal gene therapy.…”

Section: Strategies For Long-term Neuropro-tection -Gdnf As a Candidasupporting

confidence: 93%

Neuroprotective Gene Therapy for the Treatment of Inherited Retinal Degeneration

Buch¹,

MacLaren²,

Ali³

2007

CGT

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Inherited retinal degeneration (IRD) affects around 1/3000 of the population in Europe and the United States. It is a diverse group of conditions that results from mutations in any one of over 100 different genes. Many of the genes have now been identified and their functions elucidated, providing a major impetus to develop gene-based treatments. Whilst gene replacement and gene silencing strategies offer prospects for the treatment of specific inherited retinal disorders, other disorders may be less amenable to these corrective approaches. These conditions include, in particular, those associated with abnormal retinal development and those in which retinal degeneration is advanced at birth. Furthermore, the development of individualized corrective gene therapy strategies for patients with disorders due to very rare mutations may be unfeasible. However, generic gene therapy strategies that aim not to correct the gene defect but to ameliorate its consequences offer the possibility of therapies that are widely applicable across a range of conditions. One potential strategy in these cases is to halt or delay the process of cell death, so that useful visual function can be maintained throughout the lifetime of an affected individual. It has been shown in variety of experimental models over the last three decades, that neurotrophic factors have the potential to delay neuronal apoptosis. Neurotrophic factors are small proteins which have relatively short half lives and a requirement for repeated administration has limited their clinical application. Since these proteins do not ordinarily cross the blood-brain barrier, previous approaches have relied upon intrathecal infusion pumps or similar complex devices to sustain elevated neurotrophin levels within the central nervous system (CNS). However, sustained delivery through viral vector mediated expression of genes encoding neurotrophic factors may circumvent the potential side effects of repeated administration. In this review we shall explore some of the concepts of neurotrophic gene therapy and how this might be applicable to preserving vision in inherited retinal degenerations.

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Section: Strategies For Long-term Neuropro-tection -Gdnf As a Candidasupporting

confidence: 93%

Neuroprotective Gene Therapy for the Treatment of Inherited Retinal Degeneration

Buch¹,

MacLaren²,

Ali³

2007

CGT

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“…At >2.5 ng/ml, these hGDNF levels are nearly tenfold higher than those produced in previous studies that have achieved photoreceptor degeneration rescue through GDNF overexpression from retinal neurons after subretinal injection 9,10 or from intraocularly placed mouse embryonic stem cells. 15 Importantly, the expression is sustained, as ELISA measurements of GDNF in the vitreous of rats 5 months postinjection show elevated levels of the therapeutic protein (Supplementary Figure S2), which are both safe 21 and necessary for sustained rescue.…”

Section: Introductionmentioning

confidence: 94%

AAV Mediated GDNF Secretion From Retinal Glia Slows Down Retinal Degeneration in a Rat Model of Retinitis Pigmentosa

et al. 2011

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Mutations in over 80 identified genes can induce apoptosis in photoreceptors, resulting in blindness with a prevalence of 1 in 3,000 individuals. This broad genetic heterogeneity of disease impacting a wide range of photoreceptor functions renders the design of gene-specific therapies for photoreceptor degeneration impractical and necessitates the development of mutation-independent treatments to slow photoreceptor cell death. One promising strategy for photoreceptor neuroprotection is neurotrophin secretion from Müller cells, the primary retinal glia. Müller glia are excellent targets for secreting neurotrophins as they span the entire tissue, ensheath all neuronal populations, are numerous, and persist through retinal degeneration. We previously engineered an adeno-associated virus (AAV) variant (ShH10) capable of efficient and selective glial cell transduction through intravitreal injection. ShH10-mediated glial-derived neurotrophic factor (GDNF) secretion from glia, generates high GDNF levels in treated retinas, leading to sustained functional rescue for over 5 months. This GDNF secretion from glia following intravitreal vector administration is a safe and effective means to slow the progression of retinal degeneration in a rat model of retinitis pigmentosa (RP) and shows significant promise as a gene therapy to treat human retinal degenerations. These findings also demonstrate for the first time that glia-mediated secretion of neurotrophins is a promising treatment that may be applicable to other neurodegenerative conditions.

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“…65,66 Whether similar negative effects on retinal histology and function would be observed in other model of RP or in normal rat eyes, remains to be determined. To date, analyses performed 7 days after IVT injection of 100 ng GDNF in the pig, 37 8 weeks after subretinal administration of recombinant adeno-associated virus --GDNF in the mouse 11 or 1 year after IVT administration or recombinant adeno-associated virus --GDNF in the rat 67 did not mention any sign of ocular toxicity or visual function disturbances in healthy eyes. GDNF was also well tolerated in several animal models of retinal pathology (see Table 1).…”

Section: Discussionmentioning

confidence: 99%

Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose

et al. 2011

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Glial cell line-derived neurotrophic factor (GDNF) is one of the candidate molecules among neurotrophic factors proposed for a potential treatment of retinitis pigmentosa (RP). It must be administered repeatedly or through sustained releasing systems to exert prolonged neuroprotective effects. In the dystrophic Royal College of Surgeon's (RCS) rat model of RP, we found that endogenous GDNF levels dropped during retinal degeneration time course, opening a therapeutic window for GDNF supplementation. We showed that after a single electrotransfer of 30 mg of GDNF-encoding plasmid in the rat ciliary muscle, GDNF was produced for at least 7 months. Morphometric, electroretinographic and optokinetic analyses highlighted that this continuous release of GDNF delayed photoreceptors (PRs) as well as retinal functions loss until at least 70 days of age in RCS rats. Unexpectedly, increasing the GDNF secretion level accelerated PR degeneration and the loss of electrophysiological responses. This is the first report: (i) demonstrating the efficacy of GDNF delivery through non-viral gene therapy in RP; (ii) establishing the efficacy of intravitreal administration of GDNF in RP associated with a mutation in the retinal pigment epithelium; and (iii) warning against potential toxic effects of GDNF within the eye/retina.

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Long-Term Safety of GDNF Gene Delivery in the Retina

Abstract: Long-term expression of GDNF within the eyes can be achieved by intravitreal injection of rAAV vectors in the absence of morphological or functional deficits in the retina.

Cited by 10 publications

References 44 publications

Neuroprotective Gene Therapy for the Treatment of Inherited Retinal Degeneration

Neuroprotective Gene Therapy for the Treatment of Inherited Retinal Degeneration

AAV Mediated GDNF Secretion From Retinal Glia Slows Down Retinal Degeneration in a Rat Model of Retinitis Pigmentosa

Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose

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