Achromatopsia, ACHROMATOPSIA 7
Conditions
Keywords
achromatopsia, PBA, ATF6, color blindness
Brief summary
Some patients with achromatopsia, an inherited disorder characterized by partial or complete loss of color vision, carry mutations in ATF6. ATF6 is a gene that is responsible for coding a protein that acts in response to endoplasmic reticulum (ER) stress. When the ATF6 protein is mutated, retinal function decreases, contributing to color blindness. The study aims to investigate whether an already FDA-approved drug, glycerol phenylbutyrate (PBA), can improve retinal function inpatients with achromatopsia caused by ATF6 mutations. Patients will be instructed to take three doses of PBA per day at equally divided time intervals and rounded up to the nearest 0.5 mL. The total dose of PBA will be 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) and will not exceed 17.5 mL/day (19 g/day). Their condition will be monitored over the course of a minimum of 3 clinic visits that will consist of a number of retinal function tests, fundus examinations, and imaging procedures. Findings from the study could elucidate the potential for PBA to serve as a treatment for patients with ATF6-mediated a chromatopsia.
Detailed description
ATF6 has been described as an endoplasmic reticulum (ER) stress-regulated transmembrane protein that activates the transcription of molecular chaperones in response to ER stress. Patients harboring mutations in ATF6 present with decreased retinal function and are diagnosed with achromatopsia. The investigator's research group has previously demonstrated that administration of glycerol phenylbutyrate (PBA), a fatty acid compound that facilitates protein folding, can lead to enhanced retinal function in mice that are homozygous for the ATF6 mutation. This study will investigate the effects of PBA administration in two patients who carry ATF6-/- mutations and a diagnosis of achromatopsia. Enrolled subjects will undergo a minimum of 3 clinic visits that consist of a complete ophthalmic examination (best-corrected visual acuity, intraocular pressure, anterior segment examination, slit lamp and binocular fundus examination), a visual functioning questionnaire, color vision tests, contrast sensitivity tests, retinal imaging (optical coherence tomography, short wavelength autofluorescence and near-infrared autofluorescence), a macular sensitivity test (Nidek microperimetry) and full-field electroretinogram (ffERG). A blood draw will be performed at each visit to test for any indications of adverse effects from drug use. Subjects will be instructed to take 3 doses of PBA per day, totaling to a dose of 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day).
Interventions
DRUGPBA
Glycerol phenylbutyrate (PBA) is a triglyceride that consists of three molecules of phenylbutyrate linked to a glycerol backbone. It is a nitrogen-binding agent that has been approved by the Food and Drug Administration (FDA) for the treatment of urea cycle disorders. Oral supplementation of PBA demonstrated no severe side effects, and are found to be therapeutically effective in reducing ER stress. Patients will be instructed to take three doses of PBA per day at equally divided time intervals and rounded up to the nearest 0.5 mL. The total dose of PBA will be 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) and will not exceed 17.5 mL/day (19 g/day).
Sponsors
Columbia University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Two patients will receive PBA as treatment for ATF6-/- Achromatopsia.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients harboring mutations in ATF6 present with decreased retinal function
Exclusion criteria
* Patients who are minors * Patients who are pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in best corrected visual acuity (BCVA) | Baseline, 1 month, 3 months, 6 months post-PBA use | to measure changes in vision at each time point |
| Changes in contrast sensitivity | Baseline, 1 month, 3 months, 6 months post-PBA use | using Pelli Robson charts |
| Changes in color vision | Baseline, 1 month, 3 months, 6 months post-PBA use | using D50 |
| Changes in macular sensitivity | Baseline, 1 month, 3 months, 6 months post-PBA use | using microperimetry (Nidek) |
| Changes in retinal imaging | After 1 and 3 months of PBA use. If changes in retinal function is observed, an additional ophthalmic evaluation will be conducted after 6 months of PBA use | including optical coherence tomography (OCT), short wavelength autofluorescence (SW-AF), and near-infrared autofluorescence (NIR-AF) |
| Changes in Full-field Electroretinogram (ffERG) X | After 1 and 3 months of PBA use. If changes in retinal function is observed, an additional ophthalmic evaluation will be conducted after 6 months of PBA use | to measure changes in rod and cone traces |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in intraocular pressure | Baseline, 1 month, 3 months, 6 months post-PBA use | part of full ophthalmic evaluation |
| Changes in anterior segment | After 1 and 3 months of PBA use. If changes in retinal function is observed, an additional ophthalmic evaluation will be conducted after 6 months of PBA use | part of full ophthalmic evaluation |
| Changes observed in posterior segment (slit lamp and binocular fundus examination) | After 1 and 3 months of PBA use. If changes in retinal function is observed, an additional ophthalmic evaluation will be conducted after 6 months of PBA use | part of full ophthalmic evaluation |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORStephen Tsang, MD
Columbia University
Outcome results
None listed