Long-Term Effects of Retinal Gene Therapy in Childhood Blindness

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 humanRPGRtransgene 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 ofRPGRgene augmentation and substantially broaden the therapeutic window for intervention in patients withRPGR-XLRP.

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Long-Term Effects of Gene Therapy in a Novel Mouse Model of Human MFRP-Associated Retinopathy

Human Gene Therapy ◽

10.1089/hum.2018.192 ◽

2019 ◽

Vol 30 (5) ◽

pp. 632-650 ◽

Cited By ~ 3

Author(s):

Anil Chekuri ◽

Bhubanananda Sahu ◽

Venkata Ramana Murthy Chavali ◽

Marina Voronchikhina ◽

Angel Soto-Hermida ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Long Term Effects

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434. Long-Term Effects on Retinal Function and Structure Using AAV-Mediated Gene Therapy in Blind RPE65 Null Mutation Dogs

Molecular Therapy ◽

10.1016/j.ymthe.2005.06.436 ◽

2005 ◽

Vol 11 ◽

pp. S168

Keyword(s):

Gene Therapy ◽

Retinal Function ◽

Null Mutation ◽

Long Term Effects

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Adenovirus-Mediated Gene Therapy for Mucopolysaccharidosis VII: Involvement of Cross-Correction in Wide-Spread Distribution of the Gene Products and Long-Term Effects of CTLA-4Ig Coexpression

Molecular Therapy ◽

10.1006/mthe.2000.0067 ◽

2000 ◽

Vol 1 (5) ◽

pp. 406-413 ◽

Cited By ~ 29

Author(s):

Motomichi Kosuga ◽

Satori Takahashi ◽

Kyoko Sasaki ◽

Xiao-Kang Li ◽

Masayuki Fujino ◽

...

Keyword(s):

Gene Therapy ◽

Gene Products ◽

Wide Spread ◽

Long Term Effects

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Abstract 5423: rAAV-Mediated Gene Therapy with Inducible Nitric Oxide Synthase (iNOS) Affords Permanent Cardioprotection (1 Year) without Adverse Functional Consequences

Circulation ◽

10.1161/circ.118.suppl_18.s_547-d ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Qianhong Li ◽

Yiru Guo ◽

Wen-Jian Wu ◽

Qinghui Ou ◽

Santosh K Sanganalmath ◽

...

Keyword(s):

Gene Therapy ◽

Gene Transfer ◽

Viral Vector ◽

Long Term Effects ◽

Inos Gene ◽

Inos Protein Expression ◽

Functional Consequences ◽

And Function ◽

Oxide Synthase

The ultimate goal of prophylactic gene therapy is to confer permanent protection against ischemia. Although gene therapy with iNOS is known to protect against myocardial infarction at 3 days and up to 2 months, the long-term effects of iNOS gene therapy on myocardial ischemic injury and function are unknown. To address this issue, we created a recombinant adeno-associated viral vector carrying the iNOS gene (rAAV/iNOS) which enables long-lasting transgene expression. Mice received injections in anterior LV wall of rAAV/LacZ or rAAV/iNOS; 1 year later, they underwent a 30-min coronary occlusion (O) and 4 h of reperfusion (R). iNOS gene transfer resulted in elevated iNOS protein expression (+ 2.9-fold vs. LacZ group, n=6, P<0.05; Fig ) and iNOS activity (+ 3.3-fold vs. LacZ group, n=4, P<0.05) 1 year later. Infarct size (% of risk region) was dramatically reduced at 1 year after iNOS gene transfer (13.5+/−2.2%, n=12, vs. 42.9+/−2.6%, n=12, in LacZ group; Fig ). The infarct-sparing effects of iNOS gene therapy at 1 year were as powerful as those observed 24 h after ischemic PC (six 4-min O/4-min R cycles) (16.3+/−2.3%, n=8; Fig ). Importantly, compared with the LacZ group (n=11), iNOS gene transfer (n=10) had no effect on LV dimensions or function for up to 1 year (at 1 year: LVEDD 4.4+/−0.1 vs. 4.2+/−0.2 mm; LVESD 2.9+/−0.1 vs. 2.9+/−0.2 mm; FS 34+/−1.8 vs. 32+/−2.6%; EF 56+/−2.3 vs. 60+/−2.9%) (echocardiography). These data demonstrate, for the first time, that rAAV-mediated iNOS gene transfer affords long-term, probably permanent (1 year) cardioprotection without adverse functional consequences, providing a strong rationale for further preclinical testing of prophylactic gene therapy.

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Faculty Opinions recommendation of Long-term effects of systemic gene therapy in a canine model of myotubular myopathy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727472006.793553474 ◽

2018 ◽

Author(s):

Nigel Laing

Keyword(s):

Gene Therapy ◽

Canine Model ◽

Long Term Effects ◽

Myotubular Myopathy

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Limited time window for retinal gene therapy in a preclinical model of ciliopathy

Human Molecular Genetics ◽

10.1093/hmg/ddaa124 ◽

2020 ◽

Vol 29 (14) ◽

pp. 2337-2352

Author(s):

Poppy Datta ◽

Avri Ruffcorn ◽

Seongjin Seo

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Retinal Degeneration ◽

Time Window ◽

Therapeutic Effects ◽

Limited Time ◽

Term Efficacy ◽

Disease Stages ◽

Retinal Gene Therapy

Abstract Retinal degeneration is a common clinical feature of ciliopathies, a group of genetic diseases linked to ciliary dysfunction, and gene therapy is an attractive treatment option to prevent vision loss. Although the efficacy of retinal gene therapy is well established by multiple proof-of-concept preclinical studies, its long-term effect, particularly when treatments are given at advanced disease stages, is controversial. Incomplete treatment and intrinsic variability of gene delivery methods may contribute to the variable outcomes. Here, we used a genetic rescue approach to ‘optimally’ treat retinal degeneration at various disease stages and examined the long-term efficacy of gene therapy in a mouse model of ciliopathy. We used a Bardet–Biedl syndrome type 17 (BBS17) mouse model, in which the gene-trap that suppresses Bbs17 (also known as Lztfl1) expression can be removed by tamoxifen administration, restoring normal gene expression systemically. Our data indicate that therapeutic effects of retinal gene therapy decrease gradually as treatments are given at later stages. These results suggest the presence of limited time window for successful gene therapy in certain retinal degenerations. Our study also implies that the long-term efficacy of retinal gene therapy may depend on not only the timing of treatment but also other factors such as the function of mutated genes and residual activities of mutant alleles.

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