PBA Use for Treatment of ATF6-/- Patients
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Early Phase 1 |
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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: PBA treatment of ATF6-/- Achromatopsia Patients will be monitored at the baseline visit, followed by a second and third visit that will be 1 and 3 months after the initial visit. Patients will complete a standard visual functioning questionnaire and undergo a complete ophthalmic evaluation at each visit. Other visual assessments will consist of color vision testing, contrast sensitivity, retinal imaging, and macular sensitivity testing using microperimetry. Full-field electroretinogram will also be performed at the baseline visit and after 1 and 3 months of PBA use. If improvement in retinal function is observed, an additional ophthalmic evaluation will be conducted after 6 months of PBA use. A blood draw will be performed at each visit to test for any indications of adverse effects from drug use. |
Drug: PBA
Glycerol phenylbutyrate (PBA) is a triglyceride that consists of three molecules of phenylbutrate 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).
Other Names:
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Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
Criteria
Inclusion Criteria:
- Patients harboring mutations in ATF6 present with decreased retinal function
Exclusion Criteria:
-
Patients who are minors
-
Patients who are pregnant
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Edward S. Harkness Eye Institute | New York | New York | United States | 10032 |
Sponsors and Collaborators
- Columbia University
Investigators
- Principal Investigator: Stephen Tsang, MD, Professor of Ophthalmology and Professor of Pathology and Cell Biology
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- AAAR9833