PBA Use for Treatment of ATF6-/- Patients

Achromatopsia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04041232
• Other study ID #: AAAR9833
• Status: Not yet recruiting
• Phase: Early Phase 1
• Start date: May 2023
• Est. completion date: March 2024

Study information

• Verified date: March 2023
• Source: Columbia University
• Contact: Stephen Tsang, MD
• Phone: 212-342-1189
• Email: sht2[@]cumc.columbia.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 2
• Est. completion date: March 2024
• Est. primary completion date: March 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients harboring mutations in ATF6 present with decreased retinal function

Exclusion Criteria:

• Patients who are minors
• Patients who are pregnant

Related Conditions & MeSH terms

• Achromatopsia
• ACHROMATOPSIA 7
• Color Vision Defects

Intervention

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).

Locations

Country	Name	City	State
United States	Edward S. Harkness Eye Institute	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Columbia University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Changes in contrast sensitivity	using Pelli Robson charts	Baseline, 1 month, 3 months, 6 months post-PBA use
Primary	Changes in color vision	using D50	Baseline, 1 month, 3 months, 6 months post-PBA use
Primary	Changes in macular sensitivity	using microperimetry (Nidek)	Baseline, 1 month, 3 months, 6 months post-PBA use
Primary	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
Primary	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	Changes in intraocular pressure	part of full ophthalmic evaluation	Baseline, 1 month, 3 months, 6 months post-PBA use
Secondary	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
Secondary	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