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Ghazi N.G.,King Khaled Eye Specialist Hospital | Ghazi N.G.,University of Virginia | Abboud E.B.,King Khaled Eye Specialist Hospital | Nowilaty S.R.,King Khaled Eye Specialist Hospital | And 25 more authors.
Human Genetics | Year: 2016

MERTK is an essential component of the signaling network that controls phagocytosis in retinal pigment epithelium (RPE), the loss of which results in photoreceptor degeneration. Previous proof-of-concept studies have demonstrated the efficacy of gene therapy using human MERTK (hMERTK) packaged into adeno-associated virus (AAV2) in treating RCS rats and mice with MERTK deficiency. The purpose of this study was to assess the safety of gene transfer via subretinal administration of rAAV2-VMD2-hMERTK in subjects with MERTK-associated retinitis pigmentosa (RP). After a preclinical phase confirming the safety of the study vector in monkeys, six patients (aged 14 to 54, mean 33.3 years) with MERTK-related RP and baseline visual acuity (VA) ranging from 20/50 to <20/6400 were entered in a phase I open-label, dose-escalation trial. One eye of each patient (the worse-seeing eye in five subjects) received a submacular injection of the viral vector, first at a dose of 150 µl (5.96 × 1010vg; 2 patients) and then 450 µl (17.88 × 1010vg; 4 patients). Patients were followed daily for 10 days at 30, 60, 90, 180, 270, 365, 540, and 730 days post-injection. Collected data included (1) full ophthalmologic examination including best-corrected VA, intraocular pressure, color fundus photographs, macular spectral domain optical coherence tomography and full-field stimulus threshold test (FST) in both the study and fellow eyes; (2) systemic safety data including CBC, liver and kidney function tests, coagulation profiles, urine analysis, AAV antibody titers, peripheral blood PCR and ASR measurement; and (3) listing of ophthalmological or systemic adverse effects. All patients completed the 2-year follow-up. Subretinal injection of rAAV2-VMD2-hMERTK was associated with acceptable ocular and systemic safety profiles based on 2-year follow-up. None of the patients developed complications that could be attributed to the gene vector with certainty. Postoperatively, one patient developed filamentary keratitis, and two patients developed progressive cataract. Of these two patients, one also developed transient subfoveal fluid after the injection as well as monocular oscillopsia. Two patients developed a rise in AAV antibodies, but neither patient was positive for rAAV vector genomes via PCR. Three patients also displayed measurable improved visual acuity in the treated eye following surgery, although the improvement was lost by 2 years in two of these patients. Gene therapy for MERTK-related RP using careful subretinal injection of rAAV2-VMD2-hMERTK is not associated with major side effects and may result in clinical improvement in a subset of patients. © 2016, Springer-Verlag Berlin Heidelberg. Source

Wen Y.,Rose Silverthorne Retinal Degenerations Laboratory | Locke K.G.,Rose Silverthorne Retinal Degenerations Laboratory | Hood D.C.,Columbia University | Birch D.G.,Rose Silverthorne Retinal Degenerations Laboratory | Birch D.G.,University of Texas Southwestern Medical Center
Experimental Eye Research | Year: 2011

One of the characteristic signs of retinitis pigmentosa (RP) is the progressive loss of night vision. We have previously shown that the gain of rod photoreceptor activation is moderately reduced in some patients with RP, but this decrease in activation kinetics is not sufficient to account for the night blindness. Recently, single rod recording from animal models of RP showed rods under degeneration remain saturated for shorter periods than normal rods; i.e. are less able to sustain the rod photoresponse. Using paired-flash ERG, here we determine whether rod phototransduction inactivation parameters might also be abnormal in patients with RP. Inactivation parameters were derived from 13 subjects with normal vision, 16 patients with adRP, and 16 patients with autosomal recessive/isolate (rec/iso) RP. The adRP cases included 9 patients with rhodopsin mutations and 7 patients with peripherin/RDS mutations. The inactivation phase was derived using a double-flash paradigm, with a test flash of 2.7 log scot td-s followed at varying intervals by a 4.2 log scot td-s probe flash. Derived rod photoresponses to this just-saturating test flash in normal subjects exhibit a critical time to the initiation of recovery (Tsat) of 525 ± 90 (SD) ms. The values of Tsat were 336 ± 104 (SD) ms in patients with adRP (P < 0.001) and 271 ± 45 (SD) ms (P < 0.001) in patients with rec/iso RP. When Tsat values were categorized by mutations, the values were 294 ± 91 (SD) ms (P < 0.001) for rhodopsin mutations, and 389 ± 100 (SD) ms (p = 0.01) for peripherin/RDS mutations. Overall, Tsat in patients with RP was significantly correlated with the amplitude of ISCEV standard rod response (r = 0.56; P < 0.001) and the gain of the activation phase of phototransduction (r = 0.6, P < 0.001). Tsat may be a useful marker for therapeutic efficacy in future clinical trials in RP. © 2011 Elsevier Ltd. Source

Wen Y.,Rose Silverthorne Retinal Degenerations Laboratory | Locke K.G.,Rose Silverthorne Retinal Degenerations Laboratory | Hood D.C.,Columbia University | Birch D.G.,Rose Silverthorne Retinal Degenerations Laboratory | Birch D.G.,University of Texas Southwestern Medical Center
Advances in Experimental Medicine and Biology | Year: 2012

Using paired-flash electroretinogram (ERG), our goal was to determine whether the inactivation of rod phototransduction is altered in patients with Retinal Degenerative Diseases (RDDs). The rod photoresponses were derived from 18 patients with autosomal dominant retinitis pigmentosa (adRP) (n = 18), 5 patients with cone-rod dystrophy (CRD), and 4 patients with Stargardt disease. Thirteen subjects with normal eye exams served as controls. T sat, the parameter describing phototransduction inactivation, was derived using the paired-flash ERG protocol. Rod a-wave recovery initiates at 544 ± 92 ms (mean ± SD) after a just-saturating test flash in subjects with normal vision. For patients with RDDs, the rod a-wave recovery initiates at 331 ± 99 ms (autosomal dominant RP, P < 0.001, t-test), 473 ± 113 ms (CRD, P = 0.26, t-test), and 491 ± 98 ms (Stargardt disease, P = 0.38, t-test). Thus patients with adRP show earlier-than-normal photoresponse recovery, while patients with CRD or Stargardt disease typically have T sat values within the normal range. © 2012 Springer Science+Business Media, LLC. Source

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