Improvement and Decline in Vision with Gene Therapy in Childhood Blindness

Jacobson, Samuel G.; Cideciyan, Artur V.; Román, Alejandro J.; Sumaroka, Alexander; Schwartz, Sharon; Hèon, Elise; Hauswirth, William W.

doi:10.1056/nejmoa1412965

Cited by 340 publications

(279 citation statements)

References 20 publications

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“…In human clinical trials to date, AAV-vectored gene therapy for the RPE65 form of Leber congenital amaurosis (LCA) has shown improvement of some aspects of vision (36,37), but there is recent evidence in patients from two of the ongoing trials that such intervention has not been able to stem the progression rate of retinal degeneration (16,38,39). In naturally occurring canine models, both of RPE65-LCA and others, gene therapy has produced similar results: intervention after the onset of photoreceptor degeneration has not been able to modify the natural history of the disease (16) or to restore visual function unless adjunctive treatments are done (40).…”

Section: Discussionmentioning

confidence: 99%

“…So does drug development for retinal degenerative diseases run a risk of high attrition as seen with the therapy pipelines for Alzheimer and Parkinson's diseases (6, 7)? Disappointing results with sustained delivery of the neuroprotective agent ciliary neurotrophic factor (CNTF) for the treatment of early-and latestage RP in two studies (62) and evidence that patients involved in two of the gene therapy clinical trials for the RPE65 form of Leber congenital amaurosis (LCA) show unabated photoreceptor and vision loss despite initial visual improvement (16,38,39) suggest that evidence in animal models for long-term efficacy and testing at clinically relevant stages of disease are needed to improve the predictive value of preclinical studies.…”

Section: Improving the Predictive Value Of Animal Models Used To Testmentioning

confidence: 99%

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Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Beltran

Cideciyan

Iwabe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.

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Section: Discussionmentioning

confidence: 99%

Section: Improving the Predictive Value Of Animal Models Used To Testmentioning

confidence: 99%

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Beltran

Cideciyan

Iwabe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…drei Jahren langsam nachlassen und weiterer Zellenverlust sowie Abnahme der Sehleistung zu beobachten sind. Die dafür verantwortlichen Mechanismen sind noch nicht geklärt [1,10]. …”

Section: Die Größten Herausforderungen Und Zielsetzungenunclassified

“…Die jüngsten Patienten scheinen von dieser Therapie am meisten profitiert zu haben. Andere Studien zeigten eine weitere Progression des Zellverlustes auch nach dem Therapiebeginn und eine langsame Verschlechterung der Sehleistung ab drei Jahren nach der Therapie [5,10].…”

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Gentherapie zur Behandlung von Netzhauterkrankungen

Ochakovski

Bartz‐Schmidt

Fischer

2017

Medizinische Genetik

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Zusammenfassung Eine Reihe von Netzhauterkrankungen hat bekannte genetische Ursachen, die prinzipiell durch Gentherapie behandelt werden können. Diese Übersicht stellt das Prinzip und die Besonderheiten der okulären Gentherapie dar, fasst den aktuellen Stand der Forschung bis hin zur klinischen Anwendung zusammen und gibt einen Ausblick auf aktuelle Entwicklungen der Gentherapie am Auge.

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“…They reported 5,6 that the effects were waning in some patients as early as one year after treatment.…”

Section: By H E I D I L E D F O R Dmentioning

confidence: 99%