Publications by authors named "G Alex Ochakovski"

11 Publications

Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia: A Nonrandomized Controlled Trial.

JAMA Ophthalmol 2020 06;138(6):643-651

Institute for Ophthalmic Research, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany.

Importance: Achromatopsia linked to variations in the CNGA3 gene is associated with day blindness, poor visual acuity, photophobia, and involuntary eye movements owing to lack of cone photoreceptor function. No treatment is currently available.

Objective: To assess safety and vision outcomes of supplemental gene therapy with adeno-associated virus (AAV) encoding CNGA3 (AAV8.CNGA3) in patients with CNGA3-linked achromatopsia.

Design, Setting, And Participants: This open-label, exploratory nonrandomized controlled trial tested safety and vision outcomes of gene therapy vector AAV8.CNGA3 administered by subretinal injection at a single center. Nine patients (3 per dose group) with a clinical diagnosis of achromatopsia and confirmed biallelic disease-linked variants in CNGA3 were enrolled between November 5, 2015, and September 22, 2016. Data analysis was performed from June 6, 2017, to March 12, 2018.

Intervention: Patients received a single unilateral injection of 1.0 × 1010, 5.0 × 1010, or 1.0 × 1011 total vector genomes of AAV8.CNGA3 and were followed up for a period of 12 months (November 11, 2015, to October 10, 2017).

Main Outcomes And Measures: Safety as the primary end point was assessed by clinical examination of ocular inflammation. Systemic safety was assessed by vital signs, routine clinical chemistry testing, and full and differential blood cell counts. Secondary outcomes were change in visual function from baseline in terms of spatial and temporal resolution and chromatic, luminance, and contrast sensitivity throughout a period of 12 months after treatment.

Results: Nine patients (mean [SD] age, 39.6 [11.9] years; age range, 24-59 years; 8 [89%] male) were included in the study. Baseline visual acuity letter score (approximate Snellen equivalent) ranged from 34 (20/200) to 49 (20/100), whereas baseline contrast sensitivity log scores ranged from 0.1 to 0.9. All 9 patients underwent surgery and subretinal injection of AAV8.CNGA3 without complications. No substantial safety problems were observed during the 12-month follow-up period. Despite the congenital deprivation of cone photoreceptor-mediated vision in achromatopsia, all 9 treated eyes demonstrated some level of improvement in secondary end points regarding cone function, including mean change in visual acuity of 2.9 letters (95% CI, 1.65-4.13; P = .006, 2-sided t test paired samples). Contrast sensitivity improved by a mean of 0.33 log (95% CI, 0.14-0.51 log; P = .003, 2-sided t test paired samples).

Conclusions And Relevance: Subretinal gene therapy with AAV8.CNGA3 was not associated with substantial safety problems and was associated with cone photoreceptor activation in adult patients, as reflected by visual acuity and contrast sensitivity gains.

Trial Registration: Identifier: NCT02610582.
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June 2020

Retinal oedema in central retinal artery occlusion develops as a function of time.

Acta Ophthalmol 2020 Sep 10;98(6):e680-e684. Epub 2020 Feb 10.

Department of Ophthalmology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.

Purpose: Time is the key criterion in the management of non-arteritic central retinal artery occlusion (NA-CRAO). However, the precise onset of vision loss is often difficult to determine. This study aimed to evaluate the temporal changes of retinal thickness in acute NA-CRAO and the potential of this parameter to be used as a surrogate marker to estimate the onset of retinal ischaemia.

Methods: Optical coherence tomography was used to continuously assess retinal thickness and oedema progression rate in six porcine eyes. Additionally, a retrospective analysis of 12 patients with acute NA-CRAO was performed to determine association strength and progression rate between retinal thickness and onset of ischaemia. All Optical coherence tomography (OCT) scans (pigs and NA-CRAO patients) were performed within an ischaemic time frame of up to 9 hr.

Results: Retinal oedema progression rate in pigs was 25.32 µm/hr [CI 95%: 24.24-26.40 µm/hr]. Retrospective analysis of the patients revealed a strong correlation between retinal oedema and duration of ischaemia (Spearman's rho = 0.77, p = 0.004) with an estimated progression rate of 10.02 µm/hr [CI 95%: 3.30-16.74 µm/hr].

Conclusion: Retinal thickness increases with oedema formation, and ischaemia onset is strongly correlated with this structural biomarker in both, pigs and NA-CRAO patients. Prospective clinical trials will have to determine the clinical feasibility of retinal thickness measurements as a biomarker to support clinical management of NA-CRAO.
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September 2020

Efficacy and Safety of Retinal Gene Therapy Using Adeno-Associated Virus Vector for Patients With Choroideremia: A Randomized Clinical Trial.

JAMA Ophthalmol 2019 Nov;137(11):1247-1254

STZ eyetrial at the Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Tübingen, Germany.

Importance: Choroideremia (CHM) is a rare, degenerative, genetic retinal disorder resulting from mutation of the CHM gene, leading to an absence of functional ras-associated binding escort protein 1 (REP1). There is currently no approved treatment for CHM.

Objective: To assess the safety and efficacy of retinal gene therapy with an adeno-associated virus vector (AAV2) designed to deliver a functional version of the CHM gene (AAV2-REP1) for treatment of patients with choroideremia.

Design, Setting, And Participants: Tübingen Choroideremia Gene Therapy (THOR) was a single-center, phase 2, open-label randomized clinical trial. Data were collected from January 11, 2016, to February 26, 2018. Twenty-four-month data are reported for 6 men with a molecularly confirmed diagnosis of CHM. Intention-to-treat analysis was used.

Interventions: Patients received AAV2-REP1 by a single, 0.1-mL subretinal injection of 1011 genome particles during vitrectomy into 1 eye randomly assigned to receive treatment.

Main Outcomes And Measures: Primary end point was change in best-corrected visual acuity (BCVA) on the Early Treatment Diabetic Retinopathy Study chart from baseline to month 24 in the treated eye vs the control eye. Secondary end points included microperimetry variables, change in fundus autofluorescence, and spectral-domain optical coherence tomographic evaluations from baseline to month 24 in the treated eye vs the control eye.

Results: On enrollment, the mean (SD) age of the 6 men included in the study was 54.9 (4.1) years. The mean (SD) BCVA score was 60.3 (13.4) (approximately 20/63 Snellen equivalent) in the study eyes and 69.3 (20.6) (approximately 20/40 Snellen equivalent) in the control eyes. At 24 months, the BCVA change was 3.7 (7.5) in the treated eyes and 0.0 (5.1) in the control eyes (difference, 3.7; 95% CI, -7.2 to 14.5; P = .43). Mean change in retinal sensitivity was 10.3 (5.5) dB in the treated eyes and 9.7 (4.9) dB in the control eyes (difference, 0.6; 95% CI, -10.2 to 11.4; P = .74). A total of 28 adverse events were reported; all were consistent with the surgical procedure (eg, conjunctival hyperemia, foreign body sensation), and none were regarded as severe.

Conclusions And Relevance: Among 6 participants, gene therapy with AAV2-REP1 was associated with maintenance or improvement of visual acuity, although no significant difference was found from control eyes. All safety issues were associated with the surgical procedure and none were judged severe. Continued investigations could more precisely define the efficacy and safety of gene therapy with AAV2-REP1 in CHM.

Trial Registration: identifier: NCT02671539.
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November 2019

Phenotyping of Mouse Models with OCT.

Methods Mol Biol 2019 ;1834:285-291

Centre for Ophthalmology, University Eye Hospital, University of Tuebingen, Tuebingen, Germany.

Optical coherence tomography (OCT) is an invaluable technique to perform noninvasive retinal imaging in small animal models such as mice. It provides virtual cross sections that correlate well with histomorphometric data with the advantage that multiple iterative measurements can be acquired in timeline analyses to detect dynamic changes and reduce the number of animals needed per study.
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April 2019


Retina 2020 Jan;40(1):160-168

STZ Eyetrial at the Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany.

Purpose: Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1). We evaluated retinal gene therapy with an adeno-associated virus vector that used to deliver a functional version of the CHM gene (AAV2-REP1).

Methods: THOR (NCT02671539) is a Phase 2, open-label, single-center, randomized study. Six male patients (51-60 years) with CHM received AAV2-REP1, by a single 0.1-mL subretinal injection of 10 genome particles during vitrectomy. Twelve-month data are reported.

Results: In study eyes, 4 patients experienced minor changes in best-corrected visual acuity (-4 to +1 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); one gained 17 letters and another lost 14 letters. Control eyes had changes of -2 to +4 letters. In 5/6 patients, improvements in mean (95% confidence intervals) retinal sensitivity (2.3 [4.0] dB), peak retinal sensitivity (2.8 [3.5] dB), and gaze fixation area (-36.1 [66.9] deg) were recorded. Changes in anatomical endpoints were similar between study and control eyes. Adverse events were consistent with the surgical procedure.

Conclusion: Gene therapy with AAV2-REP1 can maintain, and in some cases, improve, visual acuity in CHM. Longer term follow-up is required to establish whether these benefits are maintained.
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January 2020