Gyrate AtrophyPhase 1NCT00001735
Gene Therapy for Gyrate Atrophy
A Phase 1 study testing Gene therapy in people with Gyrate Atrophy, run by National Eye Institute (NEI) at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Gyrate Atrophy
- What is being tested?
- Gene therapy
- Type of treatment
- Surgery or procedure
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 1998to Oct 2000
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
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 procedures.
Patients demonstrates progression of ocular disease due to grate atrophy evidenced by reduction in electrophysiologic testing, visual field testing or progression of retinal findings.
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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Eye Institute (NEI)
Bethesda, Maryland, 20892
About this study
Official title: Phase I Study in the Safety and Efficacy of Transduced Keratinocytes for Possible Treatment of Gyrate Atrophy
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.
Read more
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 procedure:
- Skin biopsy-A small piece of skin is surgically removed from the patient's thigh.
- 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.
- 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.
Read the detailed description
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.
- Conditions
- Gyrate Atrophy
- Being tested
- Gene therapy
- Keywords
- Gene Therapy, Graft, Ornithine, Retina, Retinovirus, Retrovirus, Skin, Gyrate Atrophy
- Medical subject headings
- Gyrate Atrophy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gene therapyProcedure or surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Dec 2002 (estimated)
- Study startApr 1998
- Study completionOct 2000
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Gyrate AtrophyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Enrolment
- 5 participants
Sponsor and investigators
- Lead sponsor
- National Eye Institute (NEI)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00001735
- Sponsor's protocol ID
- 980088
- Other IDs
- 98-EI-0088
- Status last verified
- Mar 2000
- First submitted
- 3 Nov 1999
- Last updated
- 4 Mar 2008
- Results posted
- No
Publications
Brody LC, Mitchell GA, Obie C, Michaud J, Steel G, Fontaine G, Robert MF, Sipila I, Kaiser-Kupfer M, Valle D. Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem. 1992 Feb 15;267(5):3302-7.
PubMed 1737786Kasahara M, Matsuzawa T, Kokubo M, Gushiken Y, Tashiro K, Koide T, Watanabe H, Katunuma N. Immunohistochemical localization of ornithine aminotransferase in normal rat tissues by Fab'-horseradish peroxidase conjugates. J Histochem Cytochem. 1986 Nov;34(11):1385-8. doi: 10.1177/34.11.3534076.
PubMed 3534076Rao GN, Cotlier E. Ornithine delta-aminotransferase activity in retina and other tissues. Neurochem Res. 1984 Apr;9(4):555-62. doi: 10.1007/BF00964382.
PubMed 6462326
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study in the Safety and Efficacy of Transduced Keratinocytes for Possible Treatment of Gyrate Atrophy
- ClinicalTrials.gov ID
- NCT00001735
- Acronym / sponsor ID
- 980088
- Conditions
- Gyrate Atrophy
- Keywords
- Gene Therapy, Graft, Ornithine, Retina, Retinovirus, Retrovirus, Skin, Gyrate Atrophy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 5 participants
- Lead sponsor
- National Eye Institute (NEI)US National Institutes of Health
- Study start
- Apr 1998
- Study completion
- Oct 2000
- First posted
- 10 Dec 2002 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 procedure:
- Skin biopsy-A small piece of skin is surgically removed from the patient's thigh.
- 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.
- 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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Gene therapy | Procedure or surgery | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Mar 2008.
- Background: PubMed 1737786Brody LC, Mitchell GA, Obie C, Michaud J, Steel G, Fontaine G, Robert MF, Sipila I, Kaiser-Kupfer M, Valle D. Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem. 1992 Feb 15;267(5):3302-7.
- Background: PubMed 3534076Kasahara M, Matsuzawa T, Kokubo M, Gushiken Y, Tashiro K, Koide T, Watanabe H, Katunuma N. Immunohistochemical localization of ornithine aminotransferase in normal rat tissues by Fab'-horseradish peroxidase conjugates. J Histochem Cytochem. 1986 Nov;34(11):1385-8. doi: 10.1177/34.11.3534076.
- Background: PubMed 6462326Rao GN, Cotlier E. Ornithine delta-aminotransferase activity in retina and other tissues. Neurochem Res. 1984 Apr;9(4):555-62. doi: 10.1007/BF00964382.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Gene therapy in people with Gyrate Atrophy, run by National Eye Institute (NEI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Mar 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00001735, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2008.