Clinical trial NCT01263379: Gene Transfer for Recessive Dystrophic Epidermolysis Bullosa
Official title: A Phase 1/2A Single Center Trial of Gene Transfer for Recessive Dystrophic Epidermolysis Bullosa (RDEB) Using the Drug LZRSE-Col7A1 Engineered Autologous Epidermal Sheets (LEAES)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Epidermolysis Bullosa Dystrophica
Epidermolysis Bullosa
Keywords: gene transfer
Lead sponsor: Abeona Therapeutics, Inc
Sponsor class: INDUSTRY
Collaborators: name: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
name: Stanford University
First posted: 2010-12-20
Enrollment: 12
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This trial will create a skin graft, which the investigators call "LEAES," using the patient's own skin cells that have been genetically engineered in the lab to express a missing protein called type VII collagen. The corrected cells will be transplanted back to the patient.

Detailed description: The research project involves gene transfer into keratinocytes, which are the majority of the cells in the outer layer of skin. In this gene transfer trial we plan to biopsy some skin tissue, grow the cells in a skin cell culture (sterile dishes with special fluid that allows cells to grow and multiply) and then infect the cells with a virus that we have genetically engineered to insert the correct type VII collagen gene. The cells should then make type VII collagen.

The process of inserting the correct type VII collagen gene into cells is called "gene transfer." The virus used is called a "retrovirus." The virus is made so that it only delivers the type VII collagen gene and it should not spread to other parts of the body. During the study we will check for growth of the virus.

After cells have received gene transfer, we will grow the cells in culture into a sheet of cells that look like a plastic film. We plan to graft the sheet to wounds. Grafting means we will take cells from the culture and stitch them to the patient's skin.

Eligibility criteria: Inclusion Criteria:

1. Clinical diagnosis of recessive dystrophic epidermolysis bullosa (RDEB)
2. 13 years old or older and willing and able to give assent/consent
3. Confirmation of RDEB diagnosis by immunofluorescence (IF) and electron microscopy (EM)
4. NC1\[+\] and mAb LH24 antibody staining negative
5. RDEB type VII collagen mutations in subject and carrier parents confirmed
6. At least 100 to 200 cm2 areas of open erosions on the trunk and/or extremities suitable for skin grafting
7. Able to undergo adequate anesthesia to allow grafting procedures to take place.

Exclusion Criteria:

1. Medical instability limiting ability to travel to Stanford University Medical Center
2. The presence of medical illness expected to complicate participation and/or compromise the safety of this technique, such as active infection with HIV, hepatitis B or hepatitis C, as determined by hepatitis B surface antigen screening, detection of hepatitis C antibodies, or positive result of hepatitis C polymerase chain reaction (PCR) analysis.
3. Antibodies to type VII collagen associated antigens
4. Active infection in the area that will undergo grafting
5. Evidence of systemic infection
6. Current evidence or a history of squamous cell carcinoma in the area that will undergo grafting
7. Active drug or alcohol addiction
8. Hypersensitivity to vancomycin or amikacin
9. Receipt of chemical or biological study product for the specific treatment of RDEB in the past six months
10. Positive pregnancy test or breast-feeding
11. Clinically significant abnormalities (Grade 2 or higher on the National Cancer Institute \[NCI\] toxicity scale) on laboratory tests performed prior to grafting, except for the following specific exclusionary laboratory threshold results, subject to approval or exemption by the EB physician:

    * Albumin \< 2.5 g/dL
    * Leukocytes \> 20K/uL
    * Hemoglobin \< 7.5 g/dL. Low hemoglobin will be treated at the discretion of the investigators and the EB physician.
    * Additional exceptions may be made at the discretion of the investigators and the EB physician.
12. Clinically significant abnormalities (Grade 2 or higher on the NCI toxicity scale) identified through medical history and physical examination on Day 0, with the following exceptions:

    * Anorexia, can enroll up to Grade 4 (inclusive)
    * Constipation, can enroll up to Grade 2 (inclusive)
    * Dysphagia, can enroll up to Grade 4 (inclusive)
    * Keratitis, can enroll up to Grade 4 (inclusive)
    * Bone pain, can enroll up to Grade 2 (inclusive)
    * Additional exceptions may be made at the discretion of the investigators and the EB physician.

Primary outcomes:
measure: Number of Wounds by Healing Category Per Investigator Visual Assessment
timeFrame: 3, 6, 12 and 24 months post grafting
measure: Percentage Surface Area of Wound Healing
timeFrame: 3, 6 and 12 months post grafting
Secondary outcomes:
measure: Number Participants Positive for NC2 Epitope as a Measure of Duration of Type VII Collagen Production
timeFrame: 3 months, 6 months, 12 months, 24 months post-grafting
Other outcomes:
measure: Number of Participants With Presence of Anchoring Fibrils (AF)
timeFrame: 3 months, 6 months, 12 months and 24 months post grafting
Locations:
city: Redwood City
country: United States
facility: Stanford University, School of Medicine, Dept of Dermatology
state: California
Study officials:
affiliation: Stanford University
name: Jean Tang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: So JY, Nazaroff J, Iwummadu CV, Harris N, Gorell ES, Fulchand S, Bailey I, McCarthy D, Siprashvili Z, Marinkovich MP, Tang JY, Chiou AS. Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa. Orphanet J Rare Dis. 2022 Oct 17;17(1):377. doi: 10.1186/s13023-022-02546-9.
citation: Eichstadt S, Barriga M, Ponakala A, Teng C, Nguyen NT, Siprashvili Z, Nazaroff J, Gorell ES, Chiou AS, Taylor L, Khuu P, Keene DR, Rieger K, Khosla RK, Furukawa LK, Lorenz HP, Marinkovich MP, Tang JY. Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa. JCI Insight. 2019 Oct 3;4(19):e130554. doi: 10.1172/jci.insight.130554.
citation: Siprashvili Z, Nguyen NT, Gorell ES, Loutit K, Khuu P, Furukawa LK, Lorenz HP, Leung TH, Keene DR, Rieger KE, Khavari P, Lane AT, Tang JY, Marinkovich MP. Safety and Wound Outcomes Following Genetically Corrected Autologous Epidermal Grafts in Patients With Recessive Dystrophic Epidermolysis Bullosa. JAMA. 2016 Nov 1;316(17):1808-1817. doi: 10.1001/jama.2016.15588.