Gene delivery to mitotic and postmitotic photoreceptors
            <i>Via</i>
            compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa

Cai, Xue; Conley, Shannon M.; Nash, Zack; Fliesler, Steven J.; Cooper, Mark J.; Naash, Muna I.

doi:10.1096/fj.09-139147

Cited by 106 publications

(120 citation statements)

References 42 publications

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“…We constructed CK30PEG NP-carrying (4.3 mg DNA/ml) vectors (13-14 kbp) with the human ABCA4 cDNA and the photoreceptor-specific human interphotoreceptor retinoid-binding protein (IRBP-ABCA4) promoter or the mouse opsin (MOP-ABCA4) promoter (1,2) and confirmed that the NPs carried intact plasmid (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI64833DS1). NPs carrying nonfunctional mutant ABCA4 (K969M, ref.…”

Section: Resultsmentioning

confidence: 72%

“…Compacted DNA nanoparticles (NPs) (8-10 nm in diameter) formulated with polyethylene glycol-substituted polylysine (CK30PEG) are highly efficient in transfecting postmitotic cells (1)(2)(3)(4)(5), are biodegradable (3,4), and exhibit minimal toxicity, even after repeated dosing, to the eye, lung, and brain (1,2,(5)(6)(7). In contrast with many other nonviral approaches, these NPs drive long-term gene expression (1,2) after subretinal delivery to the mouse eye, making them an excellent choice for chronic retinal degenerations such as Stargardt.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast with many other nonviral approaches, these NPs drive long-term gene expression (1,2) after subretinal delivery to the mouse eye, making them an excellent choice for chronic retinal degenerations such as Stargardt. They have recently been used to mediate phenotypic rescue in rodent models of retinitis pigmentosa, Parkinson disease, and cystic fibrosis, and were safely employed in a phase I/II clinical trial for cystic fibrosis (2,8,9).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice

Han¹,

Conley²,

Makkia³

et al. 2012

J. Clin. Invest.

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132

149

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Mutations in the photoreceptor-specific flippase ABCA4 are associated with Stargardt disease and many other forms of retinal degeneration that currently lack curative therapies. Gene replacement is a logical strategy for ABCA4-associated disease, particularly given the current success of traditional viral-mediated gene delivery, such as with adeno-associated viral (AAV) vectors. However, the large size of the ABCA4 cDNA (6.8 kbp) has hampered progress in the development of genetic treatments. Nonviral DNA nanoparticles (NPs) can accommodate large genes, unlike traditional viral vectors, which have capacity limitations. We utilized an optimized DNA NP technology to subretinally deliver ABCA4 to Abca4-deficient mice. We detected persistent ABCA4 transgene expression for up to 8 months after injection and found marked correction of functional and structural Stargardt phenotypes, such as improved recovery of dark adaptation and reduced lipofuscin granules. These data suggest that DNA NPs may be an excellent, clinically relevant gene delivery approach for genes too large for traditional viral vectors.

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Section: Resultsmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice

Han¹,

Conley²,

Makkia³

et al. 2012

J. Clin. Invest.

Self Cite

132

149

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“…Advantages of such physico-chemical approaches include the fact that there are no size limitations with respect to the transgene cassette and that the approach does not deliver additional antigens besides the DNA/DNA-binding reagents themselves. Potential disadvantages include concern about longevity of expression and efficiency of nuclear entry, although a recent report using compacted DNA nanoparticles showed evidence of marked physiologic rescue for at least 30 days after delivery (26).…”

Section: Gene Augmentation Therapy Considerationsmentioning

confidence: 99%

Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

Hollander

Black²,

Bennett³

et al. 2010

J. Clin. Invest.

183

100

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Nonsyndromic recessive retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to be incurable. Molecular genetic studies in the last two decades have revealed the underlying molecular causes in approximately two-thirds of patients. The mammalian eye has been at the forefront of therapeutic trials based on gene augmentation in humans with an early-onset nonsyndromic recessive retinal dystrophy due to mutations in the retinal pigment epithelium-specific protein 65kDa (RPE65) gene. Tremendous challenges still lie ahead to extrapolate these studies to other retinal disease-causing genes, as human gene augmentation studies require testing in animal models for each individual gene and sufficiently large patient cohorts for clinical trials remain to be identified through cost-effective mutation screening protocols.

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“…In addition, in contrast with other nonviral approaches, CK30-NPs drive long-term gene expression after subretinal delivery to the mouse eye . Given the success of CK30-NPs to mediate phenotypic rescue in rodent models of retinitis pigmentosa (Cai et al 2009(Cai et al , 2010 and their favorable safety and efficacy profile in a human clinical trial for cystic fibrosis (Konstan et al 2004). Han et al (2012) have recently tested CK30-NPs for ABCA4 delivery in the Abca4…”

Section: Nonviral Gene Delivery In Abca4-associated Diseasesmentioning

confidence: 99%

Gene Therapy of ABCA4-Associated Diseases

Auricchio

Trapani

Allikmets

2015

Cold Spring Harbor Perspectives in Medicine

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The ATP-binding cassette (ABC) transporter gene, ABCA4 (ABCR), was characterized in 1997 as the causal gene for autosomal recessive Stargardt disease (STGD1). Shortly thereafter several other phenotypes were associated with mutations in ABCA4, which now have collectively emerged as the most frequent cause of retinal degeneration phenotypes of Mendelian inheritance. ABCA4 functions as an important transporter (or "flippase") of vitamin A derivatives in the visual cycle. Several ways to alleviate the effects of the defective ABCA4 protein, which cause accumulation of 11-cis and all-trans-retinal in photoreceptors and lipofuscin in the retinal pigment epithelium, have been proposed. Although ABCA4 has proven to be a difficult research target, substantial progress through genetic, functional, and translational studies has allowed major advances in therapeutic applications for ABCA4-associated pathology, which should be available to patients in the (near) future. Here, we summarize the status of the gene therapy-based treatment options of ABCA4-associated diseases.

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Gene delivery to mitotic and postmitotic photoreceptors Via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa

Cited by 106 publications

References 42 publications

DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice

DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice

Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

Gene Therapy of ABCA4-Associated Diseases

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