This study will evaluate the safety and effectiveness of gene therapy for patients with
gyrate atrophy, an inherited condition in which areas of the retina-the inner lining of the
wall of the eye-become thin. Over several decades, this degeneration of the retina causes
tunnel vision, night blindness, and other vision problems.
Gyrate atrophy is caused by a defect in the gene responsible for producing an enzyme,
ornithine aminotransferase (OAT), that breaks down an amino acid called ornithine. As a
result, excessive ornithine buildup causes the retinal thinning. Currently, this condition
can only be treated with amino acid tablets and a very low-protein diet with limited fruits
and vegetables and more than 2,000 calories a day from carbohydrates and fats. Some
patients cannot maintain this diet, and they need another treatment. One possible
alternative is to replace the defective gene with one that functions normally.
Patients who have been followed in NEI's Ocular Genetics service may be eligible to
participate in this study. Study patients will undergo the following gene therapy
1. Skin biopsy-A small piece of skin is surgically removed from the patient's thigh.
2. Gene transfer-Skin cells called keratinocytes are taken from the biopsied tissue and
grown in the laboratory. The normal gene that produces OAT is inserted into the cells,
causing them to produce more of the enzyme.
3. Skin graft-Under local anesthesia, a patch of skin about 2 1/4 inches x 2 1/4 inches
is surgically removed from the upper thigh and some of the cells with increased OAT are
grafted back onto this area.
Patients will be followed at 1 week and 2 weeks after the procedure, then monthly for 6
months, again at 9 months and 1 year. Follow-up will continue at 1-year intervals in
patients in whom the treatment is successful. During each follow-up visit patients will
have 2 to 3 tablespoons of blood drawn for tests. A small biopsy (about 1/4 inch) of
transplanted cells will also be done at 1 week, 1 month, 3 months, 6 months, 1 year, and
each year or so thereafter. These tests will evaluate whether the treated skin cells are
producing the deficient OAT enzyme and, if so, how much and for how long. They will also
indicate whether the enzyme produced is sufficient to lower ornithine blood levels.
Patients will also undergo various eye examinations before grafting and at scheduled
follow-up visits. These tests may include electrophysiologic (ERG) testing, fundus
photographs, scanning laser ophthalmoscope, visual field test, fluorescein angiogram, visual
acuity, and manifest reaction.
The primary purpose of this phase I study is to evaluate the safety of a skin engraftment
procedure for transplanting ex-vivo transduced keratinocytes in patients with a deficiency
of the ornithine transferase gene (OAT). The safety of this procedure will be evaluated in
terms of technical complications and the immune response of the patient to the presence of
the transduced keratinocytes. Adult patients with gyrate atrophy, a disease defined by a
deficiency of OAT, who have been followed for an extended period of time at the National Eye
Institute and whose natural history is known to the investigators will be evaluated for
study enrollment. Keratinocytes, previously obtained and grown in culture from these
patients, will be transduced with a retrovirus manufactured under GMP conditions to express
the OAT gene. The autologous transduced keratinocytes will be returned to the patient on
the upper thigh in a small patch prepared to receive graft. At study defined visits, the
site integrity will be monitored and biopsies of the grafted areas will be performed. The
biopsies will provide information to evaluate the following three secondary study
objectives: 1) the ability of keratinocytes to express the OAT gene, 2) the extent and
duration of such expression, and 3) the extent to which the activity present in the
keratinocytes is sufficient to lower serum levels of ornithine.
Elevated serum ornithine level greater than or equal to 200 micro M, as measured by the
median of three values obtained monthly for two months prior to the screening visit and at
the screening visit.
Absence of OAT activity measured by western blot analysis and isolated enzyme activity in
skin biopsy samples.
Fundus findings indicative of gyrate atrophy as characterized by sharply demarcated
circular patches of chorioretinal atrophy.
Must be at least 18 years of age.
Female patients of child bearing potential must have a pregnancy test done, which
demonstrates a negative result and must agree to practice effective birth control for 12
months following study initiation, or until patch removal, whichever comes first.
Must sign and date the informed consent and is willing and able to follow study
Patients demonstrates progression of ocular disease due to grate atrophy evidenced by
reduction in electrophysiologic testing, visual field testing or progression of retinal
Patient has been offered an arginine-restricted diet and is unable to attain ornithine
levels less than 200 micro M prior to patch placement.
Patient has previously undergone a skin biopsy.
Not currently participating in other experimental protocols or therapeutic trials.
Does not have a known malignancy or chronic infection yielding immunoincompetence.
Patient must be able to maintain follow-up and follow details of the protocol.