PBA Use for Treatment of ATF6-/- Patients

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Achromatopsia; ACHROMATOPSIA 7
• Intervention / Treatment: Drug: PBA

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 Type: Interventional
• Enrollment (Anticipated): 2
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Stephen Tsang, MD; Phone Number: 212-342-1189; Email: sht2@cumc.columbia.edu
• Study Contact Backup: Name: Laura Jenny; Email: lj2539@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Edward S. Harkness Eye Institute
      • Contact: Stephen Tsang, MD; Phone Number: 212-342-1189; Email: sht2@cumc.columbia.edu
      • Principal Investigator: Stephen Tsang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients harboring mutations in ATF6 present with decreased retinal function

Exclusion Criteria:

• Patients who are minors
• Patients who are pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: Glycerol Phenylbutyrate

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Stephen Tsang, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2023
• Primary Completion (Anticipated): March 1, 2024
• Study Completion (Anticipated): March 1, 2024

Study Registration Dates

• First Submitted: July 31, 2019
• First Submitted That Met QC Criteria: July 31, 2019
• First Posted (Actual): August 1, 2019

Study Record Updates

• Last Update Posted (Actual): March 17, 2023
• Last Update Submitted That Met QC Criteria: March 15, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: PBA; achromatopsia; ATF6; color blindness
• Additional Relevant MeSH Terms: Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Eye Diseases, Hereditary; Sensation Disorders; Vision Disorders; Cone Dystrophy; Color Vision Defects; Physiological Effects of Drugs; Protective Agents; Cryoprotective Agents; Glycerol
• Other Study ID Numbers: AAAR9833

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No