Clinical Trial: Natural History Study of Patients With Leber Congenital Amaurosis Associated With Mutations in RPE65

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational

Official Title: Natural History Study of Patients With Leber Congenital Amaurosis Associated With Mutations in RPE65

Brief Summary:

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 l

Detailed Summary:

Researchers have been very successful in the continued studies with previously ascertained subjects. Further patients already on the MEH genetic database will also be recruited. Given the rarity of LCA-RPE65 the investigators will also potentially recruit patients referred to Moorfields Hospital by consultants around the World. Subjects will be assessed annually for a total of up to 5 years follow-up.

Recruitment target is approximately 15 to 25 genetically confirmed patients.

Assessments that will be undertaken depending on age, co-operation and ability to undertake the test include (see schedule of assessments):

8.1 Complete clinical ocular examination, including visual acuity testing (for near and distance), contrast sensitivity, anterior segment slit lamp examination and posterior segment slit lamp examination.

8.2 Colour fundus photography.

8.3 SDOCT imaging. In order to ensure a good volume scan minimal oversampling will be performed but undertake sufficient B scans per volume (n=128). The investigators will then do high-resolution line scans with oversampling, 1 horizontal and 1 vertical, through the centre of the fovea.

8.4 Adaptive optics imaging.

8.5 Electrophysiological assessment incorporating the protocols recommended by the International Society for Clinical Electrophysiology of Vision (ISCEV). Full-field electroretinogram (FFERG) - a measure of global retinal function - will not be undertaken if previously documented to be undetectable - the majority of patients will have undetectable FFERG. Pattern ERG (PERG) and multifocal ERG (mfERG) will be undertaken on an a
Sponsor: MeiraGTx UK II Ltd

Current Primary Outcome: Analysis of retinal structure and function [ Time Frame: 6 years ]

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


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Quality of Life Questionnaires [ Time Frame: 6 years ]
    Assessment of Visual impairment using appropriate, validated questionnaires
  • Retinal Sensitivity [ Time Frame: 6 years ]
    To be assessed in Microperimetry
  • Retinal Structural analysis with Adaptive Optics [ Time Frame: 6 years ]
    Retinal Structure analysis
  • Fundal Autofluorescence [ Time Frame: 6 years ]
    Presence or Absence
  • Assessment of Visual Fields [ Time Frame: 6 years ]
    Assessment of Visual Fields with analysis of hill of vision


Original Secondary Outcome: Same as current

Information By: MeiraGTx UK II Ltd

Dates:
Date Received: March 8, 2016
Date Started: April 2016
Date Completion: March 2021
Last Updated: June 8, 2016
Last Verified: June 2016