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Journal of Controlled Release :... Oct 2022CRISPR/Cas9-based genome-editing therapies are poised to change the clinical outcome for many diseases with validated therapeutic targets awaiting an appropriate...
CRISPR/Cas9-based genome-editing therapies are poised to change the clinical outcome for many diseases with validated therapeutic targets awaiting an appropriate delivery system. Recent advances in lipid nanoparticle (LNP) technology make them an attractive platform for the delivery of various forms of CRISPR/Cas9, including the efficient and transient Cas9/gRNA ribonucleoprotein (RNP) complexes. In this study, we initially tested our novel LNP platform by delivering pre-complexed RNPs and template DNA to cultured mouse cortical neurons, and obtained successful ex vivo genome editing. We then directly injected LNP-packaged RNPs and DNA template into the mouse cornea to evaluate in vivo delivery. For the first time, we demonstrated wide-spread genome editing in the cornea using our LNP-RNPs. The ability of our LNPs to transfect the cornea highlights the potential of our novel delivery platform to be used in CRISPR/Cas9-based genome editing therapies of corneal diseases.
Topics: Animals; CRISPR-Cas Systems; Cornea; DNA; Gene Editing; Liposomes; Mice; Nanoparticles; Ribonucleoproteins; RNA, Guide, CRISPR-Cas Systems
PubMed: 36029893
DOI: 10.1016/j.jconrel.2022.08.042 -
Indian Journal of Ophthalmology Dec 2022Aniridia is a pan-ocular genetic developmental eye disorder characterized by complete or partial iris and foveal hypoplasia, for which there is no treatment currently.... (Review)
Review
Aniridia is a pan-ocular genetic developmental eye disorder characterized by complete or partial iris and foveal hypoplasia, for which there is no treatment currently. Progressive sight loss can arise from cataracts, glaucoma, and aniridia-related keratopathy, which can be managed conservatively or through surgical intervention. The vast majority of patients harbor heterozygous mutations involving the PAX6 gene, which is considered the master transcription factor of early eye development. Over the past decades, several disease models have been investigated to gain a better understanding of the molecular pathophysiology, including several mouse and zebrafish strains and, more recently, human-induced pluripotent stem cells (hiPSCs) derived from aniridia patients. The latter provides a more faithful cellular system to study early human eye development. This review outlines the main aniridia-related animal and cellular models used to study aniridia and highlights the key discoveries that are bringing us closer to a therapy for patients.
Topics: Humans; Animals; Mice; Zebrafish; Aniridia; Iris; Cataract; Glaucoma; PAX6 Transcription Factor
PubMed: 36453299
DOI: 10.4103/ijo.IJO_316_22 -
Survey of Ophthalmology 2023Congenital aniridia is a panocular disorder that is typically characterized by iris hypoplasia and aniridia-associated keratopathy (AAK). AAK results in the progressive... (Review)
Review
Congenital aniridia is a panocular disorder that is typically characterized by iris hypoplasia and aniridia-associated keratopathy (AAK). AAK results in the progressive loss of corneal transparency and thereby loss of vision. Currently, there is no approved therapy to delay or prevent its progression, and clinical management is challenging because of phenotypic variability and high risk of complications after interventions; however, new insights into the molecular pathogenesis of AAK may help improve its management. Here, we review the current understanding about the pathogenesis and management of AAK. We highlight the biological mechanisms involved in AAK development with the aim to develop future treatment options, including surgical, pharmacological, cell therapies, and gene therapies.
Topics: Humans; Corneal Diseases; Aniridia; Cornea; Vision Disorders; Forecasting
PubMed: 37146692
DOI: 10.1016/j.survophthal.2023.04.003 -
Cureus Oct 2022Cataract is the leading cause of childhood blindness in developing countries. Early detection and treatment of childhood cataracts can reduce the burden of blindness in... (Review)
Review
Cataract is the leading cause of childhood blindness in developing countries. Early detection and treatment of childhood cataracts can reduce the burden of blindness in the nation. Often the etiology of pediatric cataract is idiopathic; however, genetics play a role in the development of congenital cataract. According to epidemiologists, one-fourth of cases of congenital cataracts are hereditary. Gene responsible for the development of cataract is identified using gene mapping, which helps to prevent future blindness in the family. Cataracts can also present with systemic disease, microphthalmia, microcornea, and aniridia. The presentation of cataracts varies in individuals, some are symptomatic while others are asymptomatic. Parents after noticing strabismus and leukocoria bring their children to an ophthalmologist. Early diagnosis can restore visual function in cases of congenital cataract. In young babies, the type of cataract is determined using slit-lamp examination and examination under anesthesia in OR. Most cases of pediatric cataracts are accidental findings during routine checkups. On direct ophthalmoscopy, red reflex is not appreciated in cases of cataracts. Advancing technology changes the ophthalmologist's approach to pediatric cataract surgery, improving postoperative refractory function. In children, minor incision surgery was preferred to heal early. An appropriate choice of intraocular lens (IOL) should be made for implantation in a child's eye to avoid postimplanted complications. Inflammation and amblyopia affect the outcome of treatment. Complications of cataract surgery include posterior capsule opacification, glaucoma, inflammation, and uveitis.
PubMed: 36381901
DOI: 10.7759/cureus.30135 -
Archivos de La Sociedad Espanola de... Nov 2021This review updates the knowledge about the morphological assessment of the foveal hypoplasia in congenital aniridia and resumes the reported genotype-phenotype... (Review)
Review
This review updates the knowledge about the morphological assessment of the foveal hypoplasia in congenital aniridia and resumes the reported genotype-phenotype correlations known to date. Congenital aniridia is a pan ocular disease. Although iris absence is considered the hallmark of this entity, foveal hypoplasia is present in 94.7%-84% of patients. A foveal morphology assessed by optical coherence tomography in which external retina structures can be identified, with presence of the lengthening of photoreceptors outer segment and a greater external retinal thickness, is associated with a better visual outcome, regardless a foveal pit is identified or not. This analysis can be performed once the external retina has completed its differentiation, by 6 years old. PAX6 mutations that introduce premature termination codon, C terminal extension or PAX6 involving deletions have been related to lesser foveal differentiation. Better foveal differentiation has been associated to non-coding PAX6 mutations.
Topics: Aniridia; Child; Fovea Centralis; Humans; Iris; PAX6 Transcription Factor; Tomography, Optical Coherence
PubMed: 34836590
DOI: 10.1016/j.oftale.2020.11.006 -
Archivos de La Sociedad Espanola de... Mar 2021This review updates the knowledge about the morphological assessment of the foveal hypoplasia in Congenital Aniridia and resumes the reported genotype-phenotype... (Review)
Review
This review updates the knowledge about the morphological assessment of the foveal hypoplasia in Congenital Aniridia and resumes the reported genotype-phenotype correlations known to date. Congenital Aniridia is a pan ocular disease. Although iris absence is considered the hallmark of this entity, foveal hypoplasia is present in 94.7-84% of patients. A foveal morphology assessed by optical coherence tomography in which external retina structures can be identified, with presence of the lengthening of photoreceptors outer segment and a greater external retinal thickness, is associated with a better visual outcome, regardless a foveal pit is identified or not. This analysis can be performed once the external retina has completed its differentiation, by 6 years old. PAX6 mutations that introduce premature termination codon, C terminal extension or PAX6 involving deletions have been related to lesser foveal differentiation. Better foveal differentiation has been associated to non-coding PAX6 mutations.
PubMed: 33736873
DOI: 10.1016/j.oftal.2020.11.025 -
American Journal of Ophthalmology Mar 2023To study the frequency and types of strabismus in congenital aniridia, the presence of associated nystagmus, foveal hypoplasia, and congenital cataracts.
PURPOSE
To study the frequency and types of strabismus in congenital aniridia, the presence of associated nystagmus, foveal hypoplasia, and congenital cataracts.
DESIGN
Prospective, single-center cohort study.
METHODS
A review was conducted of 379 medical records of congenital aniridia patients who had a follow-up at the Necker-Enfants malades University Hospital between 2006 and 2022; the target age was between 12 months and 30 years. Ophthalmologic and orthoptic assessments according to age were performed. Strabismus was further analyzed according to the type of aniridia, foveal hypoplasia, and laterality of congenital cataract.
RESULTS
Strabismus was diagnosed in 150 patients; 73 were included in the study (28 males [38%] and 45 females [62%]), with a mean age of 11.02 years. The mean follow-up was 24 months. Thirty-six (49.3%) presented with familial aniridia, and 37 (50.7%) presented with sporadic aniridia. Thirty-six (49.3%) were diagnosed with esotropia, 37 (50.7%) had exotropia. Nystagmus was detected in 70 patients (96%). Thirty-nine (53.4%) suffered from congenital cataract, 10 unilateral (25.7%) and 29 bilateral (74.3%). Foveal hypoplasia was found in 73 cases (100%); esotropia was predominant in all grades. PAX6 mutation was found in 56 patients (77%).
CONCLUSION
Strabismus is one of the clinical signs of congenital aniridia. The laterality of congenital cataracts seems to affect the type of strabismus. The grade of foveal hypoplasia has little impact on strabismus but is prevalent for nystagmus. Foveal hypoplasia affects optical focus, which is essential for binocularity; this could explain the poor binocular adjustment leading to strabismus without exotropia or esotropia predominance.
Topics: Male; Female; Humans; Child; Infant; PAX6 Transcription Factor; Paired Box Transcription Factors; Esotropia; Exotropia; Prospective Studies; Cohort Studies; Aniridia; Nystagmus, Pathologic; Cataract
PubMed: 36375586
DOI: 10.1016/j.ajo.2022.11.003