PBA Use for Treatment of ATF6-/- Patients

Study Overview
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Brief Summary
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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
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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).

Official Title
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Evaluation of Glycerol Phenylbutyrate (PBA) Use in Endoplasmic Reticulum Stress Reduction in ATF6-/- Patients

Conditions
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ACHROMATOPSIA 7, Achromatopsia

Intervention / Treatment
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* Drug: PBA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients harboring mutations in ATF6 present with decreased retinal function Exclusion Criteria: Patients who are minors Patients who are pregnant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Two patients will receive PBA as treatment for ATF6-/- Achromatopsia.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PBA treatment of ATF6-/- Achromatopsia<br>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<br>* 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).<br>* Other names: Glycerol Phenylbutyrate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in best corrected visual acuity (BCVA) | to measure changes in vision at each time point | Baseline, 1 month, 3 months, 6 months post-PBA use | 
| Changes in contrast sensitivity | using Pelli Robson charts | Baseline, 1 month, 3 months, 6 months post-PBA use | 
| Changes in color vision | using D50 | Baseline, 1 month, 3 months, 6 months post-PBA use | 
| Changes in macular sensitivity | using microperimetry (Nidek) | Baseline, 1 month, 3 months, 6 months post-PBA use | 
| Changes in retinal imaging | including optical coherence tomography (OCT), short wavelength autofluorescence (SW-AF), and near-infrared autofluorescence (NIR-AF) | 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 | 
| Changes in Full-field Electroretinogram (ffERG) X | to measure changes in rod and cone traces | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in intraocular pressure | part of full ophthalmic evaluation | Baseline, 1 month, 3 months, 6 months post-PBA use | 
| Changes in anterior segment | part of full ophthalmic evaluation | 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 | 
| Changes observed in posterior segment (slit lamp and binocular fundus examination) | part of full ophthalmic evaluation | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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achromatopsia, PBA, ATF6, color blindness