Gene Transfer for Recessive Dystrophic Epidermolysis Bullosa

• ClinicalTrials.gov Identifier: NCT01263379
• Recruitment Status: Active, not recruiting
• First Posted: December 20, 2010
• Last Update Posted: October 27, 2020
• Sponsor: Stanford University
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Abeona Therapeutics, Inc
• Information provided by (Responsible Party): Jean Yuh Tang, Stanford University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Epidermolysis Bullosa Dystrophica; Epidermolysis Bullosa	Biological: LZRSE-Col7A1 Engineered Autologous Epidermal Sheets	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: October 5, 2010
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: December 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: LEAES treatment; LZRSE-Col7A1 Engineered Autologous Epidermal Sheets (LEAES)	Biological: LZRSE-Col7A1 Engineered Autologous Epidermal Sheets; This trial will create a graft, which we call "LEAES", of the patient's own skin that has been genetically engineered in our lab to express this missing protein.; Other Name: LEAES

Outcome Measures

Primary Outcome Measures :

1. Percentage surface area of wound healing [ Time Frame: 3, 6 and 12 months post grafting ]
   Wound dimensions, including length, width, and area (in cm2), will be obtained using the Canfield system. Changes in dimensions between visits as well as changes in dimensions from baseline will be recorded. Dimensions of untreated wounded skin will be used for comparison
2. Investigator's assessment of graft [ Time Frame: 3, 6 and 12 months post grafting ]
   The graft site will be clinically evaluated with a global score of: 1) 100% to 75% healed, 2) 74% to 50% healed, 3) 49% to 25% healed, 4) 25% to 1% healed, 5) complete graft loss, or 6) unable to determine.

Secondary Outcome Measures :

1. duration of type VII collagen production [ Time Frame: 12 weeks, 25 weeks, and 52 weeks post grafting ]
   Skin biopsies will be obtained to evaluate expression of type VII collagen, both NC1 and NC2 epitopes, using immuno-electron microscopy and immuno-fluorescent light microscopy

Other Outcome Measures:

1. presence of anchoring fibrils [ Time Frame: day 14, 4 weeks, 12 weeks, 25 weeks, and 52 weeks post grafting ]
   Skin biopsies will be obtained to observe physical development of the anchoring fibrils using electron microscopy

Eligibility Criteria

• Ages Eligible for Study: 13 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

Stanford University School of Medicine

Stanford, California, United States, 94305

Sponsors and Collaborators

Stanford University

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Abeona Therapeutics, Inc

Investigators

• Principal Investigator: Jean Tang, MD, PhD; Stanford University

More Information

Additional Information:

Stanford Dermatology Website: EB Research Update 

Safety and Wound Outcomes Following Genetically Corrected Autologous Epidermal Grafts in Patients With Recessive Dystrophic Epidermolysis Bullosa. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

• Responsible Party: Jean Yuh Tang, Associate Professor of Dermatology, Stanford University
• ClinicalTrials.gov Identifier: NCT01263379
• Other Study ID Numbers: SU-10202010-7130; IND# 13708 ( Other Identifier: FDA (Investigational New Drug Application) ); R01AR055914 ( U.S. NIH Grant/Contract ); RAC Protocol # 0701-827 ( Other Identifier: NIH Recombinant DNA Advisory Committee ); eProtocol 14563 ( Other Identifier: Stanford Institutional Review Board )
• First Posted: December 20, 2010
• Last Update Posted: October 27, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Results will be submitted to scientific journals for publication and presented at scientific meetings.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jean Yuh Tang, Stanford University:

gene transfer

Additional relevant MeSH terms:

Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Skin Abnormalities; Congenital Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases; Skin Diseases, Vesiculobullous; Collagen Diseases; Connective Tissue Diseases