The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients

Autor: Mani Mahmoudian, Elena S. Nikonova, Aimee E. Willett, Puya Aravand, Manzar Ashtari, Jean Bennett, Gui-Shuang Ying, Wei Pan, Kathleen A. Marshall, Albert M. Maguire, Gloria J. Young
Rok vydání: 2017
Předmět:
Adult
Male
cis-trans-Isomerases
0301 basic medicine
medicine.medical_specialty
Visual acuity
Adolescent
genetic structures
Genetic Vectors
Leber Congenital Amaurosis
Population
Reflex
Pupillary
Retina
Article
03 medical and health sciences
0302 clinical medicine
Physical medicine and rehabilitation
Neuroimaging
medicine
Humans
Visual Pathways
Pupillary light reflex
Child
education
Visual Cortex
education.field_of_study
medicine.diagnostic_test
business.industry
Repeated measures design
Magnetic resonance imaging
Genetic Therapy
Dependovirus
Middle Aged
Magnetic Resonance Imaging
Surgery
Clinical trial
Ophthalmology
030104 developmental biology
Mutation
Female
Injections
Intraocular
medicine.symptom
Functional magnetic resonance imaging
business
Color Perception
030217 neurology & neurosurgery
Follow-Up Studies
Zdroj: Ophthalmology. 124:873-883
ISSN: 0161-6420
DOI: 10.1016/j.ophtha.2017.01.029
Popis: Purpose Gene therapy (GT) has offered immense hope to individuals who are visually impaired because of RPE65 mutations. Although GT has shown great success in clinical trials enrolling these individuals, evidence for stability and durability of this treatment over time is still unknown. Herein we explored the value of functional magnetic resonance imaging (fMRI) as an objective measure to assess independently the longevity of retinal GT. Design Individuals with RPE65 mutations who underwent GT in their worse-seeing eye in a phase 1 clinical trial received a second subretinal injection in their contralateral eye in a follow-on clinical trial. Functional magnetic resonance imaging (MRI) was performed longitudinally to assess brain responses of patients with RPE65 mutations after stimulation of their most recently treated eye before and 1 to 3 years after GT. Participants Seven participants with RPE65 mutations who were part of the follow-on clinical trial gave informed consent to participate in a longitudinal neuroimaging fMRI study. Methods All participants underwent fMRI using a 3-Tesla MRI system and a 32-channel head coil. Participants' cortical activations were assessed using a block design paradigm of contrast reversing checkerboard stimuli delivered using an MRI-compatible video system. Main Outcome Measures The primary parameters being measured in this study were the qualitative and quantitative fMRI cortical activations produced by our population in response to the visual task. Results Functional MRI results showed minimal or no cortical responses before GT. Significant increase in cortical activation lasting at least 3 years after GT was observed for all participants. Repeated measures analysis showed significant associations between cortical activations and clinical measures such as full-field light sensitivity threshold for white, red, and blue colors; visual field; and pupillary light reflex. Conclusions Participants with RPE65 mutations showed intact visual pathways, which became responsive and strengthened after treatment. Functional MRI results independently revealed the efficacy and durability of a 1-time subretinal injection. The fMRI results paralleled those recently reported during the long-term clinical evaluations of the same patients. Results from this study demonstrated that fMRI may play an important role in providing complementary information to patients' ophthalmic clinical evaluation and has usefulness as an outcome measure for future retinal intervention studies.
Databáze: OpenAIRE
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