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Assessment of Visual Function in Patients With Gyrate Atrophy Who Are Considered Candidates for Gene Replacement
Rafael C. Caruso, MD;
Robert B. Nussenblatt, MD;
Karl G. Csaky, MD, PhD;
David Valle, MD;
Muriel I. Kaiser-Kupfer, MD
Arch Ophthalmol. 2001;119:667-669.
ABSTRACT
Objective To assess the course of change of visual function outcome variables
in 5 patients with gyrate atrophy before a gene replacement therapy clinical
trial.
Methods The outcome variables selected were visual field sensitivity and electroretinogram
amplitude. The course of change of these outcome variables was determined
by calculation of their half-lives.
Results In the 4 to 6 years during which each patient was followed up for this
study, median visual field half-lives were 17.0 years (static perimetry) and
11.4 years (kinetic perimetry). Median electroretinogram half-lives were 16.0
years (maximal response) and 10.7 years (flicker response).
Conclusions The course of the decline of visual function outcome variables is frequently
slow. Thus, a long-term clinical trial would be required to assess the efficacy
of the intervention in the preservation of visual function.
INTRODUCTION
GYRATE ATROPHY (GA) is a chorioretinal dystrophy characterized by progressive
development of atrophic areas in the choroid and retina. The molecular basis
of GA is a mutation of the ornithine-delta-aminotransferase (OAT) gene,1 and its biochemical hallmark
is hyperornithinemia. Results in humans2 and
in a mouse model of GA3 indicate that reduction
of ornithine plasma concentration slows or prevents further retinal degeneration.
One potential approach to achieve this aim is to create an ornithine "sink,"
by introducing the OAT gene into a cell population,
and thereby reduce ornithine concentration.
Between November 3, 1993, and April 10, 1994, skin keratinocytes of
5 patients diagnosed as having GA were harvested by performing a 2 x
1-cm elliptical skin biopsy with the use of local anesthesia. The purpose
of this procedure was to determine whether the normal OAT gene could be introduced into these cells, which could then be returned
to the donor's skin to act as a sink. Laboratory studies to determine the
feasibility of introducing the gene were performed,4
and ongoing research will determine the viability of the modified cells before
a possible skin transplantation. In preparation for a clinical trial, and
while these studies were being carried out, the patients' visual function
was followed up during the intervening 4 to 6 years by measuring, among other
variables, their visual acuity, visual field (VF), and electroretinogram (ERG).
Herein, we report the changes in visual function during this 4- to 6-year
period.
PATIENTS AND METHODS
All patients included in this study gave informed consent after the
research project had been approved by the National Eye Institute, Bethesda,
Md, institutional review board.
The 2 main outcome variables used to assess visual function were VF
sensitivity and ERG amplitude. Although other aspects of visual function were
measured in our patients, outcome variables that reflect central visual function
(visual acuity, dark adaptation, and color vision) were not analyzed in this
study, because they may remain stable despite progressive loss of peripheral
retinal function. Central 30° VFs were measured with a Humphrey Field
Analyzer (Humphrey Instruments, San Leandro, Calif), using the threshold 30-2
program with a full threshold strategy. A global VF score was obtained using
the summation of sensitivity values in the 76 points tested by this program.
Kinetic perimetry was performed with a Goldmann perimeter, and the area of
a representative isopter was measured.5 The
isopter obtained with stimulus I4e was used in patients 1, 4, and 5. In patients
2 and 3, the isopter obtained with stimulus V4e was used because of their
marked VF contraction. Electroretinograms were recorded following the standard
procedure recommended by the International Society for Clinical Electrophysiology
of Vision.6 The amplitude of maximal retinal
responses (mixed rod- and cone-mediated responses elicited by the standard
flash after dark adaptation) and of flicker responses (cone-mediated responses
elicited by the standard flash at a 30-Hz rate after light adaptation) was
measured in 4 of the 5 patients. In patient 2, low ERG amplitude precluded
the use of the standardized ERG, so the amplitude of flicker ERGs elicited
using the micro-ERG technique7 was used instead.
With all techniques, the half-life of the outcome variable, ie, the
number of years required for VF score or ERG amplitude to decline to 50% of
its value, was used to follow the course of the chorioretinal dystrophy. Half-lives
of visual function outcome variables were calculated by fitting the data points
with the model
where t represents time (in years); Vt, the magnitude
of the outcome variable at time t; V0, initial magnitude; and k, half-life (in
years). The period examined was from the biopsy date to the last visit.
RESULTS
Table 1 presents data on
the 5 patients, including the date of biopsy, the date of the last visit,
and visual acuity on these 2 dates. The second and third columns of this table
identify the specific OAT gene alleles present in
each patient.8 Cataract surgery was performed
on patient 3 in the left eye and the right eye in 1988 and 1989, respectively.
Patient 5 underwent cataract surgery on the left eye in 1989.
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Table 1. Patient Characteristics
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In 3 patients (patients 1, 3, and 4), there was a good agreement between
the severity of ophthalmoscopic findings and the abnormality of visual function
variables. However, in the remaining 2 patients, the severity of visual loss
exceeded the degree predictable by fundus appearance. Therefore, visual function
variables, rather than ophthalmoscopic findings, were used to quantify progression.
Table 2 lists the half-lives
of all visual function variables in all 5 patients. The median VF half-life
was 17.0 years for static perimetry and 11.4 years for kinetic perimetry.
The median ERG amplitude half-life was 16.0 years for the maximal response
and 10.7 years for the flicker response. An example of the course of a single
visual function variable (ERG maximal retinal response amplitude) in patient
4 is depicted in Figure 1. This
figure shows that the exponential model adequately described the course of
the decline in magnitude of this variable.
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Table 2. Half-Life (in Years) of Visual Function Outcome Variables
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Electroretinogram maximal retinal response amplitude in patient 4
as a function of time after biopsy. Circles indicate data for the right eye;
triangles, left eye. The lines passing through the data points correspond
to the model described in the text. The half-life of this variable was 5.4
years for the right eye and 10.3 years for the left eye.
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In 2 patients (patients 1 and 4), the VF and ERG outcome variables had
similar half-lives. In patient 2, no ERG amplitude decay could be detected
in the left eye (his most severely affected eye). This was probably because
the severity of the dystrophy had effected a decline in ERG amplitude beyond
a value that could be reliably assessed, even with the sensitive technique
used for this purpose. In patient 3, no decay in central VF sensitivity could
be observed in the left eye. Similarly, in patient 5, maximal response amplitude
did not show a measurable decay in the right eye. In both patients, a slow
decay of this outcome variable was observed in the fellow eye. This apparent
interocular difference was probably because of the slow decline in magnitude
of the variable being measured, so that the observation time was short relative
to its half-life. Patient 5 was the only patient in this sample with a ring
scotoma. Therefore, the central 30° static perimetry measurement identified
only the central island of vision, while kinetic perimetry and both ERG measurements
reflected the function of the much larger peripheral VF.
COMMENT
Little information exists about the natural history of visual function
variables (visual acuity, VF, and ERG) as a function of age in GA. An article9 describing the heterogeneity of a group of 29 Finnish
patients with GA concludes that the natural history is variable. The experience
gathered in our laboratory gives further evidence of this heterogeneity.10
The earliest detectable outcome of a gene replacement clinical trial
for GA would be a modification in plasma ornithine concentration. However,
the primary therapeutic objective of such a clinical trial is the preservation
of visual function. Therefore, outcome measures that assess the intervention's
effect on visual function are more relevant. Because the atrophic lesions
of GA first appear in the peripheral retina, diagnostic techniques that measure
overall retinal function, such as perimetry or electroretinography results,
are more appropriate than methods that only assess central retinal function.
The use of the half-life of a given visual function variable as an estimator
allows comparisons between patients with different degrees of visual loss
and comparisons between different outcome variables.
The decline in visual function outcome variables in these 5 patients
with GA, although relentless, is slow: the median half-life of the outcome
variables assessed exceeded 10 years. In this small sample, it was not possible
to relate decay in visual function to median level of plasma ornithine. Given
the slow course of the deterioration in visual function, a long-term clinical
trial will be required to determine the efficacy of any intervention technique,
including gene replacement therapy. The selection of those patients who demonstrate
a more rapid course of disease progression, ie, with a shorter half-life of
the outcome variables, would reduce the time required to assess the effect
of an intervention. Before an intervention, a knowledge of the rate of decay
of visual function is essential to assess its efficacy.
AUTHOR INFORMATION
Accepted for publication December 15, 2000.
We are grateful for the assistance provided by Patrick Lopez in the
compilation of the database that tabulates clinical data for the patients
included in this study.
Corresponding author and reprints: Rafael C. Caruso, MD, Ophthalmic
Genetics and Visual Function Branch, National Eye Institute, National Institutes
of Health, Bldg 10, Room 10N226, 10 Center Dr, MSC 1860, Bethesda, MD 20892-1860
(e-mail: rccaruso{at}helix.nih.gov).
From the Ophthalmic Genetics and Visual Function Branch (Drs Caruso
and Kaiser-Kupfer) and Laboratory of Immunology (Drs Nussenblatt and Csaky),
National Eye Institute, National Institutes of Health, Bethesda, Md; and Howard
Hughes Medical Institute Research Laboratories, The Johns Hopkins University
School of Medicine, Baltimore, Md (Dr Valle).
REFERENCES
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1. Mitchell GA, Looney JE, Brody LC, et al. Human ornithine-delta-aminotransferase: cDNA cloning and analysis of
the structural gene. J Biol Chem. 1988;263:14288-14295.
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2. Kaiser-Kupfer MI, Caruso RC, Valle D. Gyrate atrophy of the choroid and retina: long-term reduction of ornithine
slows retinal degeneration. Arch Ophthalmol. 1991;109:1539-1548.
ABSTRACT
3. Wang T, Steel G, Milam AH, Valle D. Correction of ornithine accumulation prevents retinal degeneration
in a mouse model of gyrate atrophy of the choroid and retina. Proc Natl Acad Sci U S A. 2000;97:1224-1229.
FREE FULL TEXT
4. Sullivan DM, Jensen TG, Taichman LB, Csaky KG. Ornithine-delta-aminotransferase expression and ornithine metabolism
in cultured epidermal keratinocytes: toward metabolic sink therapy for gyrate
atrophy. Gene Ther. 1997;4:1036-1044.
FULL TEXT
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5. Weleber RG, Tobler WR. Computerized quantitative analysis of kinetic visual fields. Am J Ophthalmol. 1986;101:461-468.
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