Natural History Study of Patients With Leber Congenital Amaurosis Associated With Mutations in RPE65
| Status: | Recruiting |
|---|---|
| Healthy: | No |
| Age Range: | 3 - Any |
| Updated: | 6/10/2016 |
| Start Date: | April 2016 |
| End Date: | March 2021 |
| Contact: | Anna Morka, MSc |
| Email: | anna.morka@athena-vision.com |
| Phone: | 02037252350 |
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unpublished data).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 .
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 .
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 annual basis
to determine change in central retinal function over time (often residual central function
till late in disease) - but will not be repeated once found to be undetectable.
8.6 Visual Field Testing. The Octopus 900 perimeter will be used. Static full-field testing
will be undertaken employing the GATE strategy, and size V test targets. Further analysis
will be undertaken to model the entire hill-of-vision which will enhance the information
obtained with full-field static perimetry.
8.7 Mesopic and Scotopic Microperimetry.
8.8 Colour vision testing.
8.9 Vision guided mobility. This will be assessed by measuring the ability of each subject
to navigate a simple route in a range of controlled illuminances.
8.10 Quality of Life Questionnaire.
8.11 Blood tests. Molecular confirmation of a mutation within the RPE65 gene by an
accredited laboratory may be undertaken.
Specific Aims of the study
Perform detailed phenotyping, including autofluorescence imaging, microperimetry, AO and OCT
imaging, spectral sensitivity and visual field testing, both in previously ascertained
patients and newly identified subjects.
Obtain OCT and AO images using the latest high-resolution technology in order to gain
insights into the in vivo retinal structure and compare these with the functional data
obtained
Thereby establish well-characterised cohorts of individuals with RPE65-LCA.
To use the information gained to provide more accurate advice to patients and assist in
identifying potential participants, time points to intervene, and efficacy endpoints that
may be used in planned interventions.
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 annual basis
to determine change in central retinal function over time (often residual central function
till late in disease) - but will not be repeated once found to be undetectable.
8.6 Visual Field Testing. The Octopus 900 perimeter will be used. Static full-field testing
will be undertaken employing the GATE strategy, and size V test targets. Further analysis
will be undertaken to model the entire hill-of-vision which will enhance the information
obtained with full-field static perimetry.
8.7 Mesopic and Scotopic Microperimetry.
8.8 Colour vision testing.
8.9 Vision guided mobility. This will be assessed by measuring the ability of each subject
to navigate a simple route in a range of controlled illuminances.
8.10 Quality of Life Questionnaire.
8.11 Blood tests. Molecular confirmation of a mutation within the RPE65 gene by an
accredited laboratory may be undertaken.
Specific Aims of the study
Perform detailed phenotyping, including autofluorescence imaging, microperimetry, AO and OCT
imaging, spectral sensitivity and visual field testing, both in previously ascertained
patients and newly identified subjects.
Obtain OCT and AO images using the latest high-resolution technology in order to gain
insights into the in vivo retinal structure and compare these with the functional data
obtained
Thereby establish well-characterised cohorts of individuals with RPE65-LCA.
To use the information gained to provide more accurate advice to patients and assist in
identifying potential participants, time points to intervene, and efficacy endpoints that
may be used in planned interventions.
Inclusion Criteria:
- Patients with RPE65 associated retinal dystrophy
- Minimum subject age of 3 years
- Able to give consent/parent or guardian able to give consent
Exclusion Criteria:
- Patients unable or unwilling to undertake consent or clinical testing
We found this trial at
2
sites
Ann Arbor, Michigan 48105
Principal Investigator: John Heckenlively
Phone: 734-232-9167
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