Behind the Lab Door

Vision response to dopamine replacement

Institution: University of Wisconsin, Madison

Author/principal investigator: Michael C. Struck, MD

Abstract/statement of the trial’s goals

The purpose of the study is to evaluate and document physiologic and functional changes in visual performance and retinal function of patients diagnosed with albinism (a dopamine deficiency state) following a trial of oral levodopa/carbidopa treatment.

ClinicalTrials.gov identifier: NCT01663935

Study population: 50

Inclusion criteria

Clinical diagnosis of oculocutaneous albinism
Age older than 3 years and weight more than 25 lbs.

Exclusion criteria

Ocular only albinism
Ocular pathology other than albinism
Neurologic disease, history of myocardial infarction, history of clinical depression, pregnancy

Enrollment status: Currently recruiting participants

A note from the institution regarding the value of this trial

Albinism is a major cause of severe visual impairment. Patients affected with this condition have a permanent visual disability. In tyrosinase-negative albinism OCA1 (the most common type), melanosomes do not contain melanin because they lack tyrosinase, the enzyme that stimulates melanin production. These patients also tend to have the worst visual prognosis.

Recently, work in several areas of dopamine deficient states (Parkinson’s disease, cocaine withdrawal disorder, phenylketonuria) has shown that retinal tissue is one of the richest in the concentration of dopamine. Indeed, 15 different visual functions and 13 types of dopamine retinal pathologies have been attributed in some way to the retinal dopamine system. The production of melanin, at the cellular level, requires the biochemical conversion of tyrosine to eumelanin. The first step in this biochemical pathway is the conversion of tyrosine to dopamine by the tyrosinase enzyme. Dietary levels of dopamine do not pass the blood-brain barrier to reach the retina. The extent to which the absence of dopamine in the retina of patients with albinism affects their visual function is unknown.

Entrance into the study is dependent upon clinical evidence of decreased or absent pigmentation in skin, hair and eyes. Additionally, all patients enrolled in the study will be requested to undergo genotyping (TYR gene) of their form of albinism. This study will have an intent-to-treat goal. Anyone who fits the inclusion criteria regardless of baseline logMAR vision or type of oculocutaneous albinism will be entered in the study. The goal will be to have 50 patients enrolled over 3 years.

This study has a pretest-posttest design in order to determine if improvement in vision is in response to replacement of deficiency (dopamine). Change in visual acuity as measured in logMAR by Snellen or sweep visual evoked potential after 3 months of treatment is the primary outcome. Electroretinography and optical coherence tomography will be critical determinants to confirm vision improvement as a result of improved retinal function, but they are not primary outcome data. Additionally, patients with albinism have been shown to have impaired color vision and contrast sensitivity. It is unclear if these visual functions will be affected by treatment; therefore, data will be analyzed to determine if there is a treatment effect other than on visual acuity alone.

These data provide strong rationale for a phase 2 pilot study to assess the potential efficacy of L-Dopa on visual performance in patients with albinism.

Trial of oral valproic acid for retinitis pigmentosa

Institution: Retina Foundation of the Southwest, Dallas

Author/principal investigator: David G. Birch, PhD

Abstract/statement of the trial’s goals

The objectives of this study are to evaluate the efficacy of valproic acid (VPA) to both slow the progression of visual function loss and/or to restore visual function in patients with autosomal dominant retinitis pigmentosa and to collect safety and tolerability information.

ClinicalTrials.gov identifier: NCT 01233609

Study population: 90

Inclusion criteria

Age 18 years or older, no upper age limit
Male subjects and non-childbearing female subjects must weigh 40 kg or more and 158.9 kg or less; female subjects of childbearing potential must weigh 40 kg or more and 74.9 kg or less.
Diagnosis of retinitis pigmentosa
Visual acuity of 35 letters or greater in at least one eye as measured by the EVA-ETDRS (equivalent to 20/200 on a Snellen chart)
Genotyped as autosomal dominant form of retinitis pigmentosa
Female subjects of childbearing potential and male subjects able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse, or must commit to practice at least two acceptable methods of contraception to minimize the chance of pregnancy during the study and for the 13-week period after stopping the study drug
Female subjects of childbearing potential must have a negative urine pregnancy test at study entry and throughout the duration of the study
Willingness to comply with the protocol

Exclusion criteria

Medical problems that make consistent follow-up over the treatment period unlikely (eg, stroke, severe myocardial infarction, end-stage malignancy), or in general a poor medical risk because of other systemic diseases or active uncontrolled infections
Other retinal diseases: glaucoma, retinal inflammatory disease (cystoid macular edema is allowable), cataract worse than +2 nuclear sclerosis or herpes simplex virus of the eye
Intact visual field of 5° or less
Subject unable to provide reliable perimetry measurements in both eyes for both static and kinetic visual field, as determined by the reading center
Diabetes
History of cancer (other than non-melanoma skin cancer) diagnosed or requiring treatment within the past 2 years
A hemoglobin concentration, a platelet count or an absolute neutrophil count below the lower limit of normal at study entry
Suspected liver dysfunction determined by having liver function values elevated above the upper limit of normal
History of pancreatitis by clinical features and/or laboratory abnormalities in the last 12 months
Renal dysfunction based on serum creatinine (MDRD) equation
Urea cycle disorders
History of neurological conditions including epilepsy, brain injury, encephalitis or any organic brain syndrome
History of schizophrenia, schizoaffective disorder, bipolar disorder, suicidality or organic mental disorders
Currently receiving VPA or other anti-convulsants
Sensitive to or have ever had an allergic reaction to VPA
Sensitive to or have ever had an allergic reaction to peanuts (peanut oil is an inactive ingredient in VPA capsules and the placebo)
Has taken one of the disallowed drugs at least 2 weeks prior to randomization
Pregnant women
Lactating mothers who are breastfeeding
Retinitis pigmentosa patients involved in other clinical trials within the last 3 months
Require enrollment by consent of a legally authorized representative
Persons who are unable to read are not allowed to consent for themselves or others to participate in this study
The potential participant lives in the same household as a current participant in this protocol

PAGE BREAK

Enrollment status: Currently recruiting participants

A note from the institution regarding the value of this trial

Autosomal dominant retinitis pigmentosa is a progressive form of retinal degeneration that begins in childhood with night blindness. Subsequent visual field constriction can lead to classic tunnel vision and eventual blindness. With the exception of vitamin A supplementation to slow progression, there is no treatment currently available.

Autosomal dominant retinitis pigmentosa is genetically heterogeneous, with mutations in more than 20 genes known to be causative. Many of the mutations result in misfolded protein, which is often retained in the endoplasmic reticulum. The unfolded protein response (UPR) is a cellular stress response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. The UPR attempts to restore normal function by halting translation and increasing the production of molecular chaperones involved in protein folding. If unsuccessful, the UPR can lead to cell death through apoptosis.

VPA is a promising potential treatment for autosomal dominant retinitis pigmentosa. Work in the laboratory suggests that VPA may be capable of increasing the yield of properly folded proteins such as rhodopsin. Also, because it is a potent inhibitor of the inflammatory response pathway and cell death, VPA is an intriguing candidate as a retinal disease treatment.

The VPA trial is enrolling 90 patients with autosomal dominant retinitis pigmentosa at six research centers in the United States. Each patient will be randomized to VPA or placebo and followed for 12 months. The primary outcome measure is kinetic visual field area as measured with the Octopus 900 perimeter (Haag-Streit). The study is sponsored by the Foundation Fighting Blindness Clinical Research Institute with the Casey Eye Institute at Oregon Health and Science University as the reading center.