Browsing by Subject "Blindness"

Now showing 1 - 3 of 3
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    ItemOpen Access
    AAV Gene Therapy for MPS1-associated Corneal Blindness.
    (Scientific reports, 2016-02-22) Vance, Melisa; Llanga, Telmo; Bennett, Will; Woodard, Kenton; Murlidharan, Giridhar; Chungfat, Neil; Asokan, Aravind; Gilger, Brian; Kurtzberg, Joanne; Samulski, R Jude; Hirsch, Matthew L
    Although cord blood transplantation has significantly extended the lifespan of mucopolysaccharidosis type 1 (MPS1) patients, over 95% manifest cornea clouding with about 50% progressing to blindness. As corneal transplants are met with high rejection rates in MPS1 children, there remains no treatment to prevent blindness or restore vision in MPS1 children. Since MPS1 is caused by mutations in idua, which encodes alpha-L-iduronidase, a gene addition strategy to prevent, and potentially reverse, MPS1-associated corneal blindness was investigated. Initially, a codon optimized idua cDNA expression cassette (opt-IDUA) was validated for IDUA production and function following adeno-associated virus (AAV) vector transduction of MPS1 patient fibroblasts. Then, an AAV serotype evaluation in human cornea explants identified an AAV8 and 9 chimeric capsid (8G9) as most efficient for transduction. AAV8G9-opt-IDUA administered to human corneas via intrastromal injection demonstrated widespread transduction, which included cells that naturally produce IDUA, and resulted in a >10-fold supraphysiological increase in IDUA activity. No significant apoptosis related to AAV vectors or IDUA was observed under any conditions in both human corneas and MPS1 patient fibroblasts. The collective preclinical data demonstrate safe and efficient IDUA delivery to human corneas, which may prevent and potentially reverse MPS1-associated cornea blindness.
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    Unmasking Proteolytic Activity for Adult Visual Cortex Plasticity by the Removal of Lynx1.
    (The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015-09) Bukhari, Noreen; Burman, Poromendro N; Hussein, Ayan; Demars, Michael P; Sadahiro, Masato; Brady, Daniel M; Tsirka, Stella E; Russo, Scott J; Morishita, Hirofumi

    Unlabelled

    Experience-dependent cortical plasticity declines with age. At the molecular level, experience-dependent proteolytic activity of tissue plasminogen activator (tPA) becomes restricted in the adult brain if mice are raised in standard cages. Understanding the mechanism for the loss of permissive proteolytic activity is therefore a key link for improving function in adult brains. Using the mouse primary visual cortex (V1) as a model, we demonstrate that tPA activity in V1 can be unmasked following 4 d of monocular deprivation when the mice older than 2 months are raised in standard cages by the genetic removal of Lynx1, a negative regulator of adult plasticity. This was also associated with the reduction of stubby and thin spine density and enhancement of ocular dominance shift in adult V1 of Lynx1 knock-out (KO) mice. These structural and functional changes were tPA-dependent because genetic removal of tPA in Lynx1 KO mice can block the monocular deprivation-dependent reduction of dendritic spine density, whereas both genetic and adult specific inhibition of tPA activity can ablate the ocular dominance shift in Lynx1 KO mice. Our work demonstrates that the adult brain has an intrinsic potential for experience-dependent elevation of proteolytic activity to express juvenile-like structural and functional changes but is effectively limited by Lynx1 if mice are raised in standard cages. Insights into the Lynx1-tPA plasticity mechanism may provide novel therapeutic targets for adult brain disorders.

    Significance statement

    Experience-dependent proteolytic activity of tissue plasminogen activator (tPA) becomes restricted in the adult brain in correlation with the decline in cortical plasticity when mice are raised in standard cages. We demonstrated that removal of Lynx1, one of negative regulators of plasticity, unmasks experience-dependent tPA elevation in visual cortex of adult mice reared in standard cages. This proteolytic elevation facilitated dendritic spine reduction and ocular dominance plasticity in adult visual cortex. This is the first demonstration of adult brain to retain the intrinsic capacity to elevate tPA in an experience-dependent manner but is effectively limited by Lynx1. tPA-Lynx1 may potentially be a new candidate mechanism for interventions that were shown to activate plasticity in adult brain.
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    ItemOpen Access
    Visual loss after corrective surgery for pediatric scoliosis: incidence and risk factors from a nationwide database.
    (The spine journal : official journal of the North American Spine Society, 2016-04) De la Garza-Ramos, Rafael; Samdani, Amer F; Sponseller, Paul D; Ain, Michael C; Miller, Neil R; Shaffrey, Christopher I; Sciubba, Daniel M

    Background context

    Perioperative visual loss (POVL) after spinal deformity surgery is an uncommon but severe complication. Data on the incidence and risk factors of this complication after corrective surgery in the pediatric population are limited.

    Purpose

    The present study aimed to investigate nationwide estimates of POVL after corrective surgery for pediatric scoliosis.

    Study design

    This is a retrospective study that uses a nationwide database.

    Patient sample

    The sample includes 42,339 patients under the age of 18 who underwent surgery for idiopathic scoliosis.

    Outcome measures

    The outcome measures were incidence of POVL and risk factors.

    Methods

    Patients under the age of 18 who underwent elective surgery for idiopathic scoliosis between 2002 and 2011 were identified using the Nationwide Inpatient Sample database. The incidence of POVL (ischemic optic neuropathy, central retinal artery occlusion, or cortical blindness) was estimated after application of discharge weights. Demographics, comorbidities, and operative parameters were compared between patients with and without visual loss. A multivariate logistic regression was performed to identify significant risk factors for POVL development. No funds were received in support of this work.

    Results

    The incidence of POVL was 1.6 per 1,000 procedures (0.16%). Patients with visual loss were significantly more likely to be younger and male, have Medicaid as insurance, and undergo fusion of eight or more spinal levels compared with patients without visual loss. Following multivariate analysis, older patients (odds ratio [OR]: 0.84; 95% confidence interval [CI]: 0.77-0.91) and female patients (OR: 0.08; 95% CI: 0.04-0.14) were significantly less likely to develop POVL compared with younger and male patients. On the other hand, having Medicaid as insurance (OR: 2.13;95% CI: 1.32-3.45), history of deficiency anemia (OR: 8.64; 95% CI: 5.46-14.31), and fusion of eight or more spinal levels (OR: 2.40; 95% CI: 1.34-4.30) were all independently associated with POVL.

    Conclusions

    In this nationwide study, the incidence of POVL after scoliosis surgery in patients under the age of 18 was estimated at 0.16%, similar to the rate reported in adult patients. Cortical blindness accounted for all cases of POVL in the present study. Younger patients, patients with history of deficiency anemia, and patients undergoing long-segment fusions may be at increased risk of POVL after corrective surgery for pediatric scoliosis.