BEstrophin 1 Treatment Trial on the Effectiveness of Ravicti (BETTER)
Lead Research Organisation:
University of Manchester
Department Name: School of Biological Sciences
Abstract
This study will investigate whether the drug Ravicti is a therapeutic treatment for bestrophinopathies that are a group of untreatable inherited retinal dystrophies leading to sight loss.
Bestrophinopathies are the result of mutations in a protein called bestrophin. Bestrophin's function is a channel for the passage of chloride ions across the surface of the pigmented cells at the back of the retina. Mutations in bestrophin reduce the flow of chloride ions which results in the abnormal function of the pigmented cells, which in turn disrupts normal function of the adjacent photoreceptor cells, so causing sight loss. Bestrophin activity is easily measured in the clinic by the electrooculogram (EOG) which is characteristically abnormal in bestrophinopathy patients. Thus in this study the EOG is a proxy measure of bestrophin function.
Ravicti is an approved drug for the treatment of urea cycle disorders that has a secondary function in restoring activity to proteins with a mutation that affects their normal function. How Ravicti works in this regard is unknown. We will test whether giving Ravicti to patients with a bestrophinopathy increases the function of their mutant bestrophin protein as determined by whether their EOG improves.
We will first measure the EOG in the trial participants to establish a baseline value before dosing them with Ravicti for 7 days. We will then measure the EOG again to see if it (i.e. bestrophin function) has improved. Patients will then then be Ravicti-free for 21 days before measuring the EOG again to see whether it has returned to the baseline value. Each patient will also undergo the same schedule using a placebo instead of Ravicti. The patients (and investigators) will not know whether they are receiving Ravicti or the placebo. This will allow us to determine whether any improvement in the EOG is due to Ravicti or is a coincidence resulting from just being part of the study.
This study aims to determine if Ravicti may be a treatment for a group of inherited conditions that results in sight loss and that currently have no treatment options. To help facilitate this goal we will publish our results in the scientific literature and will present our findings at conferences.
Bestrophinopathies are the result of mutations in a protein called bestrophin. Bestrophin's function is a channel for the passage of chloride ions across the surface of the pigmented cells at the back of the retina. Mutations in bestrophin reduce the flow of chloride ions which results in the abnormal function of the pigmented cells, which in turn disrupts normal function of the adjacent photoreceptor cells, so causing sight loss. Bestrophin activity is easily measured in the clinic by the electrooculogram (EOG) which is characteristically abnormal in bestrophinopathy patients. Thus in this study the EOG is a proxy measure of bestrophin function.
Ravicti is an approved drug for the treatment of urea cycle disorders that has a secondary function in restoring activity to proteins with a mutation that affects their normal function. How Ravicti works in this regard is unknown. We will test whether giving Ravicti to patients with a bestrophinopathy increases the function of their mutant bestrophin protein as determined by whether their EOG improves.
We will first measure the EOG in the trial participants to establish a baseline value before dosing them with Ravicti for 7 days. We will then measure the EOG again to see if it (i.e. bestrophin function) has improved. Patients will then then be Ravicti-free for 21 days before measuring the EOG again to see whether it has returned to the baseline value. Each patient will also undergo the same schedule using a placebo instead of Ravicti. The patients (and investigators) will not know whether they are receiving Ravicti or the placebo. This will allow us to determine whether any improvement in the EOG is due to Ravicti or is a coincidence resulting from just being part of the study.
This study aims to determine if Ravicti may be a treatment for a group of inherited conditions that results in sight loss and that currently have no treatment options. To help facilitate this goal we will publish our results in the scientific literature and will present our findings at conferences.
Technical Summary
We will investigate whether Ravicti is a therapeutic treatment for bestrophinopathies, a group of untreatable inherited retinal dystrophies leading to sight loss.
Autosomal dominant Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) result from missense mutations in bestrophin 1, a Cl- channel in the retinal pigment epithelium (RPE). These mutations result in absent or reduced Cl- conductance, characteristically manifesting as an abnormal electrooculogram (EOG). This routine clinical test measures the electrical potential difference between the apical and basolateral aspects of the RPE during light and dark adaptation. In this study it will serve a proxy measure of bestrophin 1 function.
4-phenylbutyate (4PBA) is licenced for the treatment of urea cycle disorders. It has a secondary action of restoring cellular function to mutant proteins. The mode of action is unknown but 4PBA may act as a chemical chaperone or induce the expression of cellular chaperones to help mutant proteins attain their correct tertiary structure and escape endoplasmic reticulum (ER) degradation. 4PBA may also decrease the stringency of ER retention of misfolded proteins so allowing the correct trafficking of functional mutant proteins. We have shown 4PBA fully restores Cl- conductance to mutant ARB bestrophin 1 and partially restores function to mutant BVMD bestrophin 1 in cell models and patient RPE derived from stem cells.
In a double-blind trial we will dose bestrophinopathy patients with Ravicti, a pro-drug of 4PBA, for 7 days to test whether the EOG improves compared to the baseline level. After 21 days off-drug the EOG will be repeated to determine whether it returns to baseline. Each patient will undergo the same schedule with a placebo.
To assist the drive towards a therapeutic solution, we will publish our results in the ophthalmic and other clinical literature and plan to present our findings at national and international conferences.
Autosomal dominant Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) result from missense mutations in bestrophin 1, a Cl- channel in the retinal pigment epithelium (RPE). These mutations result in absent or reduced Cl- conductance, characteristically manifesting as an abnormal electrooculogram (EOG). This routine clinical test measures the electrical potential difference between the apical and basolateral aspects of the RPE during light and dark adaptation. In this study it will serve a proxy measure of bestrophin 1 function.
4-phenylbutyate (4PBA) is licenced for the treatment of urea cycle disorders. It has a secondary action of restoring cellular function to mutant proteins. The mode of action is unknown but 4PBA may act as a chemical chaperone or induce the expression of cellular chaperones to help mutant proteins attain their correct tertiary structure and escape endoplasmic reticulum (ER) degradation. 4PBA may also decrease the stringency of ER retention of misfolded proteins so allowing the correct trafficking of functional mutant proteins. We have shown 4PBA fully restores Cl- conductance to mutant ARB bestrophin 1 and partially restores function to mutant BVMD bestrophin 1 in cell models and patient RPE derived from stem cells.
In a double-blind trial we will dose bestrophinopathy patients with Ravicti, a pro-drug of 4PBA, for 7 days to test whether the EOG improves compared to the baseline level. After 21 days off-drug the EOG will be repeated to determine whether it returns to baseline. Each patient will undergo the same schedule with a placebo.
To assist the drive towards a therapeutic solution, we will publish our results in the ophthalmic and other clinical literature and plan to present our findings at national and international conferences.
