Gene Transfer for Recessive Dystrophic Epidermolysis Bullosa

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)

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.

Study Overview

• Status: Completed
• Conditions: Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica
• Intervention / Treatment: Biological: LZRSE-Col7A1 Engineered Autologous Epidermal Sheets

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 Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Redwood City, California, United States, 94063
      • Stanford University, School of Medicine, Dept of Dermatology

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: LEAES

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Wounds by Healing Category Per Investigator Visual Assessment	The graft site was clinically evaluated by the investigator with a global score of: 1) 100% to 75% healed, 2) 74% to 50% healed, 3) 49% or less healed with 100% meaning completely healed.	3, 6, 12 and 24 months post grafting
Percentage Surface Area of Wound Healing	Percentage of wound area 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	3, 6 and 12 months post grafting

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number Participants Positive for NC2 Epitope as a Measure of Duration of Type VII Collagen Production	Skin biopsies were obtained to evaluate expression of type VII collagen, NC2 epitope, using immuno-electron microscopy and immuno-fluorescent light microscopy.	3 months, 6 months, 12 months, 24 months post-grafting

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Presence of Anchoring Fibrils (AF)	Skin biopsies were obtained to observe physical development of the anchoring fibrils using electron microscopy	3 months, 6 months, 12 months and 24 months post grafting

Collaborators and Investigators

• Sponsor: Abeona Therapeutics, Inc
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Stanford University
• Investigators: Principal Investigator: Jean Tang, MD, PhD, Stanford University

Publications and helpful links

General Publications

• 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.

Helpful Links

• Stanford Dermatology Website: EB Research Update
• Safety and Wound Outcomes Following Genetically Corrected Autologous Epidermal Grafts in Patients With Recessive Dystrophic Epidermolysis Bullosa.

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2010
• Primary Completion (Actual): March 9, 2022
• Study Completion (Actual): March 9, 2022

Study Registration Dates

• First Submitted: December 15, 2010
• First Submitted That Met QC Criteria: December 17, 2010
• First Posted (Estimated): December 20, 2010

Study Record Updates

• Last Update Posted (Actual): August 22, 2023
• Last Update Submitted That Met QC Criteria: August 4, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: gene transfer
• Additional Relevant MeSH Terms: Skin Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin Diseases, Genetic; Skin Diseases, Vesiculobullous; Skin Abnormalities; Collagen Diseases; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica
• Other Study ID Numbers: SU-10202010-7130; 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)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Results will be submitted to scientific journals for publication and presented at scientific meetings.
• IPD Sharing Time Frame: Study protocol is attached to this submission and will be available per ClinicalTrials.gov timeline.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No