Natural History Study of Patients With Leber Congenital Amaurosis Associated With Mutations in RPE65
The inherited retinal dystrophies are a clinically and genetically heterogeneous group of conditions, which often present in childhood. These disorders can be usefully divided according to whether they (i) are stationary or progressive; and (ii) exhibit predominantly rod or cone involvement, or central receptor disease. The underlying molecular genetic basis of the majority of monogenic inherited retinal disease has now been characterised.
Leber Congenital Amaurosis (LCA) is a diagnosis for a group of severe, autosomal recessively inherited rod - cone dystrophies that typically result in complete visual loss in the third or fourth decade of life. One form, LCA2, is caused by a mutation in the gene encoding RPE56, an RPE-specific 65-kDa isomerase. Non-functional RPE65 results in photoreceptor cells that are unable to respond to light resulting in these patients being visually impaired.
Proof of principle studies for RPE65 gene replacement therapy has been demonstrated with the use of recombinant adeno-associated virus serotype 2 (rAAV2/2) vectors in animal models. Furthermore clinical trials of gene replacement therapy in RPE65 associated LCA (RPE65-LCA) have shown significant promise. All three clinical trials showed improvement in visual function over the first year, however longer term follow up demonstrated progressive visual loss and that initial improvements were not maintained.
Greater efficacy was noted in animal models and we feel the relatively lower efficacy of treatment in participants was most likely due to insufficient production of RPE65 protein from AAV2/2 hRPE65 in the human eye. As the maximal tolerated vector dose had been reached for AAV2/2 hRPE65, an optimised therapeutic vector (AAV2/5-OPTIRPE65) has been developed to drive higher transgene expression levels. (Professor Robin Ali and Prof James Bainbridge - unpublished data).
In preparation for human clinical trials, a detailed prospective phenotypic study will be undertaken to investigate the natural history of RPE65-LCA. Such a study will help identify suitable patients for therapeutic intervention. Furthermore through greater phenotyping an optimal window for intervention and specific parameters to help quantify effect and identify clinical end points may have been ascertained .
Leber Congenital Amaurosis
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||Natural History Study of Patients With Leber Congenital Amaurosis Associated With Mutations in RPE65|
- Analysis of retinal structure and function [ Time Frame: 6 years ] [ Designated as safety issue: No ]Retinal structure will be analysed using state of the art Adaptive optics and SD-OCT and Fundal autofluorescence. This will be correlated with assessment of visual acuity, psychophysical visual assessment, visual mobility, retinal sensitivity and visual fields
- Quality of Life Questionnaires [ Time Frame: 6 years ] [ Designated as safety issue: No ]Assessment of Visual impairment using appropriate, validated questionnaires
- Retinal Sensitivity [ Time Frame: 6 years ] [ Designated as safety issue: No ]To be assessed in Microperimetry
- Retinal Structural analysis with Adaptive Optics [ Time Frame: 6 years ] [ Designated as safety issue: No ]Retinal Structure analysis
- Fundal Autofluorescence [ Time Frame: 6 years ] [ Designated as safety issue: No ]Presence or Absence
- Assessment of Visual Fields [ Time Frame: 6 years ] [ Designated as safety issue: No ]Assessment of Visual Fields with analysis of hill of vision
|Study Start Date:||April 2016|
|Estimated Study Completion Date:||March 2021|
|Estimated Primary Completion Date:||March 2021 (Final data collection date for primary outcome measure)|
Please refer to this study by its ClinicalTrials.gov identifier: NCT02714816
|Contact: Anna Morka, MScemail@example.com|
|Contact: Julie Bakobakifirstname.lastname@example.org|
|United States, Michigan|
|Kellogg Eye Center||Not yet recruiting|
|Ann Arbor, Michigan, United States, MI 48105|
|Contact: Adrienne Chen 734-232-9167 email@example.com|
|Contact: Anna Morka 02037252350 firstname.lastname@example.org|
|Principal Investigator: John Heckenlively|
|Moorfields Eye Hospital||Recruiting|
|London, United Kingdom|
|Contact: Neruban Kumaran, Dr email@example.com|
|Contact: Sophie Connor 02075662821 firstname.lastname@example.org|
|Principal Investigator: Michel Michealides, Prof|
|Principal Investigator:||Michel Michealides, Prof||UCL/Moorfileds|