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Evaluation of Italian Patients with Leber Congenital Amaurosis due to AIPL1 Mutations Highlights the Potential Applicability of Gene Therapy
- Publisher :
- ASSOC RESEARCH VISION OPHTHALMOLOGY INC
-
Abstract
- PURPOSE. To evaluate the suitability of gene delivery-based approaches as potential treatment of Leber Congenital Amaurosis 4 (LCA4) due to AIPL1 mutations. METHODS. Genomic DNA from patients was analyzed using a microarray chip and direct sequencing. A detailed clinical evaluation including fundus autofluorescence (FAF) and optical coherence tomography (OCT) was performed in patients with AIPL1 mutations. Aipl1 null mice and porcine eyes were subretinally injected with adeno-associated viral (AAV) vectors harboring the human AIPL1 coding sequence. RESULTS. We identified ten LCA4 patients with mutations in AIPL1. The p.W278X sequence variation was the one most frequently found. Clinical assessment revealed common features including diffuse retinal dystrophies and maculopathy. However, OCT showed partially retained photoreceptors in extra-macular regions at all ages. The FAF was elicitable at the posterior pole and absent in the fovea. AAV-mediated gene transfer in Aipl1 -/- mice was associated with restoration of AIPL1 and βPDE expression in photoreceptors and protection from degeneration. Administration of a clinically relevant dose of AAV2/8-AIPL1 to the pre-clinical large porcine retina resulted in high level of AIPL1 photoreceptor expression in the absence of toxicity. CONCLUSIONS. Using advanced imaging diagnostics we showed that maculopathy is a main feature of LCA4. We identified retinal areas at the posterior pole with surviving photoreceptors present even in adult LCA4 patients, which could be the target of gene therapy. The possible use of gene therapy for LCA4 is additionally supported by the protection from photoreceptor degeneration observed in Aipl 1-/- mice and by the high levels of photoreceptor transduction in the absence of toxicity observed following AAV2/8 delivery to the large porcine retina. PMID: 21474771 [PubMed - as supplied by publisher]
- Subjects :
- Pathology
Microarray
genetic structures
PHOTORECEPTOR TRANSDUCTION
Genetic enhancement
Posterior pole
Leber Congenital Amaurosis
Sus scrofa
chemistry.chemical_compound
Mice
0302 clinical medicine
Child
RETINA
Oligonucleotide Array Sequence Analysis
Mice, Knockout
0303 health sciences
HUMAN
AAV
Middle Aged
3. Good health
medicine.anatomical_structure
Italy
Child, Preschool
Retinal Dystrophies
Tomography, Optical Coherence
Adult
medicine.medical_specialty
Adolescent
Genetic Vectors
Gene delivery
Biology
03 medical and health sciences
Young Adult
medicine
Electroretinography
Animals
Humans
Eye Proteins
030304 developmental biology
Adaptor Proteins, Signal Transducing
Aged
Retina
PIG
Retinal
Genetic Therapy
medicine.disease
eye diseases
Disease Models, Animal
chemistry
030221 ophthalmology & optometry
Maculopathy
sense organs
Carrier Proteins
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....dc666e4083e5ccd1121641f3f89ef376