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CompletedNCT01263379Updated Aug 22, 2023Results posted

Gene Transfer for Recessive Dystrophic Epidermolysis Bullosa

A Phase 1/2 interventional study of LZRSE-Col7A1 Engineered Autologous Epidermal Sheets in Epidermolysis Bullosa Dystrophica and Epidermolysis Bullosa, sponsored by Abeona Therapeutics, Inc. Completed at 1 site in United States. Open to participants aged 13 Years and older. Per ClinicalTrials.gov, last updated 2023-08-22.

Sponsored by Abeona Therapeutics, Inc · Phase 1/2, Interventional, and Treatment

Phase
Phase 1/2
Study type
Interventional
Enrollment
12
Allocation
Not applicable
Ages
13 Years and older
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Epidermolysis Bullosa Dystrophica
  • Epidermolysis Bullosa

Keywords

  • gene transfer
03

Who can participate

Ages eligible
13 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
04

Study design

Phase
Phase 1 / Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
12 participants (actual)

Study arms

  • Experimental
    LEAES treatment

    LZRSE-Col7A1 Engineered Autologous Epidermal Sheets (LEAES)

    Biological: LZRSE-Col7A1 Engineered Autologous Epidermal Sheets

Interventions

  • BiologicalLZRSE-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.

    Also known as: LEAES

05

What researchers measure

Primary outcomes

  1. 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.

    Time frame: 3, 6, 12 and 24 months post grafting

  2. 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

    Time frame: 3, 6 and 12 months post grafting

Secondary outcomes

  1. 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.

    Time frame: 3 months, 6 months, 12 months, 24 months post-grafting

Other outcomes

  1. Number of Participants With Presence of Anchoring Fibrils (AF)

    Skin biopsies were obtained to observe physical development of the anchoring fibrils using electron microscopy

    Time frame: 3 months, 6 months, 12 months and 24 months post grafting

06

Results

Posted Jul 10, 2023

Participant flow

Participant flow — Overall Study
MilestoneLEAES Treatment
Started7
Completed7
Not completed0

Outcome measures

PrimaryNumber 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.

Time frame:
3, 6, 12 and 24 months post grafting
Reported as:
Count of units · wounds
Number of Wounds by Healing Category Per Investigator Visual Assessment
woundsLEAES Treatment
3 months — Global Score of 100% to 75%35
3 months — Global Score of 74% to 50%5
3 months — Global Score of 49% or less2
6 months — Global Score of 100% to 75%28
6 months — Global Score of 74% to 50%3
6 months — Global Score of 49% or less11
12 months — Global Score of 100% to 75%19
12 months — Global Score of 74% to 50%11
12 months — Global Score of 49% or less12
24 months — Global Score of 100% to 75%26
24 months — Global Score of 74% to 50%5
24 months — Global Score of 49% or less11
PrimaryPercentage 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

Time frame:
3, 6 and 12 months post grafting
Reported as:
Number · percentage of wound area
Percentage Surface Area of Wound Healing
percentage of wound area3 Months Post LEAES Treatment6 Months Post LEAES Treatment12 Months Post LEAES Treatment
GT04, Wound A100100100
GT04, Wound B100100100
GT04, Wound C100100100
GT04, Wound D10010097.5
GT04, Wound E100100100
GT04, Wound Z - induced1003590
GT05, Wound A9690.678.6
GT05, Wound B9881.666.5
GT05, Wound C91.57192
GT05, Wound D93.585.587.5
GT05, Wound E9674.675.7
GT05, Wound Z - induced100100100
GT07, Wound A93.59670
GT07, Wound B89.89926
GT07, Wound C99322
GT07, Wound D96.67100—
GT07, Wound E89.4594.5100
GT07, Wound F999795
GT08, Wound A705412
GT08, Wound B98.78148
GT08, Wound C1005544
GT08, Wound D827329
GT08, Wound E1008410
GT08, Wound F7048.831
GT09, Wound A9210085
GT09, Wound B100100100
GT09, Wound C797478.56
GT09, Wound D1008278.67
GT09, Wound E10010098.7
GT09, Wound F927678.6
SecondaryNumber 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.

Time frame:
3 months, 6 months, 12 months, 24 months post-grafting
Reported as:
Count of participants · Participants
Number Participants Positive for NC2 Epitope as a Measure of Duration of Type VII Collagen Production
ParticipantsLEAES Treatment
3 months — Positive for NC27
3 months — Negative for NC20
3 months — Not done0
6 months — Positive for NC25
6 months — Negative for NC22
6 months — Not done0
12 months — Positive for NC22
12 months — Negative for NC24
12 months — Not done1
24 months — Positive for NC22
24 months — Negative for NC21
24 months — Not done4
Other pre-specifiedNumber of Participants With Presence of Anchoring Fibrils (AF)

Skin biopsies were obtained to observe physical development of the anchoring fibrils using electron microscopy

Time frame:
3 months, 6 months, 12 months and 24 months post grafting
Reported as:
Count of participants · Participants
Number of Participants With Presence of Anchoring Fibrils (AF)
ParticipantsLEAES Treatment
3 months — Positive for AFs6
3 months — Negative for AFs1
3 months — Not done0
6 months — Positive for AFs5
6 months — Negative for AFs2
6 months — Not done0
12 months — Positive for AFs3
12 months — Negative for AFs3
12 months — Not done1
24 months — Positive for AFs1
24 months — Negative for AFs1
24 months — Not done5

Adverse events

Collected over 2 years post receiving LEAES cell sheets. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
LEAES Treatment0/7 (0%)2/7 (28.6%)7/7 (100%)
Most frequent serious events
Most frequent serious events
EventLEAES Treatment
Neoplasms benign, malignant and unspecified, squamous cell carcinomaSkin and subcutaneous tissue disorders2/7
Most frequent other events
Most frequent other events
EventLEAES Treatment
Wound infectionSkin and subcutaneous tissue disorders6/7
PruritusSkin and subcutaneous tissue disorders3/7
PainSkin and subcutaneous tissue disorders2/7
Wound complicationSkin and subcutaneous tissue disorders1/7
Postoperative hemorrhageSurgical and medical procedures1/7

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)LEAES Treatment
<=18 years0
Between 18 and 65 years7
>=65 years0
Sex: Female, Male
Sex: Female, Male(Participants)LEAES Treatment
Female2
Male5
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)LEAES Treatment
Hispanic or Latino3
Not Hispanic or Latino4
Unknown or Not Reported0
Race (NIH/OMB)
Race (NIH/OMB)(Participants)LEAES Treatment
American Indian or Alaska Native0
Asian0
Native Hawaiian or Other Pacific Islander0
Black or African American0
White7
More than one race0
Unknown or Not Reported0
Region of Enrollment
Region of Enrollment(Participants)LEAES Treatment
United States7
07

Study locations

1 site
  • Stanford University, School of Medicine, Dept of Dermatology
    Redwood City, California 94063, United States
08

References and documents

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. PubMed 36253825 ↗
  • 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. PubMed 31578311 ↗
  • 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. PubMed 27802546 ↗

Study documents

  • Protocol and statistical analysis plan · May 13, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Results will be submitted to scientific journals for publication and presented at scientific meetings.

Supporting information: Study protocol

09

Registry details

Key details

Study ID
NCT01263379
Lead sponsor
Abeona Therapeutics, Inc
Collaborators
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Stanford University
Responsible party
Sponsor
First posted
Dec 20, 2010
Start date
Oct 5, 2010
Primary completion
Mar 9, 2022
Completion
Mar 9, 2022
Results posted
Jul 10, 2023
Last update
Aug 22, 2023

Study contacts

Jean Tang, MD, PhD
principal investigator · Stanford University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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