Dataset Information

Dual ABCA4-AAV Vector Treatment Reduces Pathogenic Retinal A2E Accumulation in a Mouse Model of Autosomal Recessive Stargardt Disease.

ABSTRACT: Autosomal recessive Stargardt disease is the most common inherited macular degeneration in humans. It is caused by mutations in the retina-specific ATP binding cassette transporter A4 (ABCA4) that is essential for the clearance of all-trans-retinal from photoreceptor cells. Loss of this function results in the accumulation of toxic bisretinoids in the outer segment disk membranes and their subsequent transfer into adjacent retinal pigment epithelium (RPE) cells. This ultimately leads to the Stargardt disease phenotype of increased retinal autofluorescence and progressive RPE and photoreceptor cell loss. Adeno-associated virus (AAV) vectors have been widely used in gene therapeutic applications, but their limited cDNA packaging capacity of ?4.5?kb has impeded their use for transgenes exceeding this limit. AAV dual vectors were developed to overcome this size restriction. In this study, we have evaluated the in vitro expression of ABCA4 using three options: overlap, transplicing, and hybrid ABCA4 dual vector systems. The hybrid system was the most efficient of these dual vector alternatives and used to express the full-length ABCA4 in Abca4-/- mice. The full-length ABCA4 protein correctly localized to photoreceptor outer segments. Moreover, treatment of Abca4-/- mice with this ABCA4 hybrid dual vector system resulted in a reduced accumulation of the lipofuscin/N-retinylidene-N-retinylethanolamine (A2E) autofluorescence in vivo, and retinal A2E quantification supported these findings. These results show that the hybrid AAV dual vector option is both safe and therapeutic in mice, and the delivered ABCA4 transgene is functional and has a significant effect on reducing A2E accumulation in the Abca4-/- mouse model of Stargardt disease.

SUBMITTER: Dyka FM

PROVIDER: S-EPMC6854433 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dual <i>ABCA4</i>-AAV Vector Treatment Reduces Pathogenic Retinal A2E Accumulation in a Mouse Model of Autosomal Recessive Stargardt Disease.

Dyka Frank M FM Molday Laurie L LL Chiodo Vince A VA Molday Robert S RS Hauswirth William W WW

Human gene therapy 20190930 11

Autosomal recessive Stargardt disease is the most common inherited macular degeneration in humans. It is caused by mutations in the retina-specific ATP binding cassette transporter A4 (ABCA4) that is essential for the clearance of all-<i>trans</i>-retinal from photoreceptor cells. Loss of this function results in the accumulation of toxic bisretinoids in the outer segment disk membranes and their subsequent transfer into adjacent retinal pigment epithelium (RPE) cells. This ultimately leads to t ...[more]

PMID: 31418294

Similar Datasets

Project description:ObjectiveTo provide a comprehensive overview of all detected mutations in the ABCA4 gene in Spanish families with autosomal recessive retinal disorders, including Stargardt's disease (arSTGD), cone-rod dystrophy (arCRD), and retinitis pigmentosa (arRP), and to assess genotype-phenotype correlation and disease progression in 10 years by considering the type of variants and age at onset.DesignCase series.ParticipantsA total of 420 unrelated Spanish families: 259 arSTGD, 86 arCRD, and 75 arRP.MethodsSpanish families were analyzed through a combination of ABCR400 genotyping microarray, denaturing high-performance liquid chromatography, and high-resolution melting scanning. Direct sequencing was used as a confirmation technique for the identified variants. Screening by multiple ligation probe analysis was used to detect possible large deletions or insertions in the ABCA4 gene. Selected families were analyzed further by next generation sequencing.Main outcome measuresDNA sequence variants, mutation detection rates, haplotypes, age at onset, central or peripheral vision loss, and night blindness.ResultsOverall, we detected 70.5% and 36.6% of all expected ABCA4 mutations in arSTGD and arCRD patient cohorts, respectively. In the fraction of the cohort where the ABCA4 gene was sequenced completely, the detection rates reached 73.6% for arSTGD and 66.7% for arCRD. However, the frequency of possibly pathogenic ABCA4 alleles in arRP families was only slightly higher than that in the general population. Moreover, in some families, mutations in other known arRP genes segregated with the disease phenotype.ConclusionsAn increasing understanding of causal ABCA4 alleles in arSTGD and arCRD facilitates disease diagnosis and prognosis and also is paramount in selecting patients for emerging clinical trials of therapeutic interventions. Because ABCA4-associated diseases are evolving retinal dystrophies, assessment of age at onset, accurate clinical diagnosis, and genetic testing are crucial. We suggest that ABCA4 mutations may be associated with a retinitis pigmentosa-like phenotype often as a consequence of severe (null) mutations, in cases of long-term, advanced disease, or both. Patients with classical arRP phenotypes, especially from the onset of the disease, should be screened first for mutations in known arRP genes and not ABCA4.

Dataset Information

Dual ABCA4-AAV Vector Treatment Reduces Pathogenic Retinal A2E Accumulation in a Mouse Model of Autosomal Recessive Stargardt Disease.

Publications

Dual <i>ABCA4</i>-AAV Vector Treatment Reduces Pathogenic Retinal A2E Accumulation in a Mouse Model of Autosomal Recessive Stargardt Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets