Safety Study of Gene-modified Autologous Fibroblasts in Recessive Dystrophic Epidermolysis Bullosa

Phase I Study of Lentiviral-mediated COL7A1 Gene-modified Autologous Fibroblasts in Adults With Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of blistering skin disease caused by mutations in COL7A1 gene. This study aims to assess the safety of intradermal injections of gene-modified autologous fibroblasts in 5-10 adults with RDEB.

Study Overview

• Status: Completed
• Conditions: Recessive Dystrophic Epidermolysis Bullosa
• Intervention / Treatment: Drug: Gene-modified autologous fibroblasts

Detailed Description

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of blistering skin disease caused by mutations in COL7A1 gene. This study aims to assess the safety of intradermal injections of gene-modified autologous fibroblasts in 5-10 adults with RDEB.

This is an open-label single-centre phase I study with primary objective to evaluate the adverse and serious adverse events over 12 months' follow-up period. Secondary objectives include (1) analysis of type VII collagen (C7) expression and morphology of anchoring fibrils in the injected areas of the skin; (2) analysis of immune response to newly expressed C7.

Each study participant will receive three intradermal injections of COL7A1 gene-modified autologous fibroblasts on Day 0 only. Each subject will undergo an initial screening including a physical examination and assessment of disease severity. Blood analyses and skin biopsies will be performed at various time points as per the monitoring schedule over 12 months.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Guy's and St Thomas' NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Clinical and genetic diagnosis of RDEB with confirmed bi-allelic COL7A1 mutations.
2. A reduced number or morphologically abnormal anchoring fibrils confirmed by TEM.
3. At least 5x8cm of intact skin on the trunk and/or extremities that is suitable for cell injections.
4. Able to undergo local anaesthesia.
5. Subjects aged ≥ 17 years and able to give informed consent prior to the first study intervention.

Exclusion Criteria:

1. Subjects who received other investigational medicinal products within 6 months prior to enrolment into this study.
2. Past medical history of biopsy proven skin malignancy.
3. Subjects who have received immunotherapy including oral corticosteroids (Prednisolone >1mg/kg) for more than one week (intranasal and topical preparations are permitted) or chemotherapy within 60 days of enrolment into this study.
4. Known allergy to any of the constituents of the investigational medicinal product (IMP).

5. Subjects with BOTH:

   • positive serum antibodies to C7 confirmed by ELISA and
   • positive IIF with binding to the base of salt split skin.
6. Subjects who are pregnant or of child-bearing potential who are neither abstinent nor practising an acceptable means of contraception when this is in line with the usual and preferred lifestyle of the subject, as determined by the Investigator, for 12 months after the cell injections.
7. Subjects with positive results for HIV, Hepatitis B, Hepatitis C, HTLV or Syphilis.

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: Gene-modified autologous fibroblasts; 3 intradermal injections of COL7A1 gene-modified autologous fibroblasts will be administered on day 0 only.	Drug: Gene-modified autologous fibroblasts; 3 intradermal injections of COL7A1 gene-modified autologous fibroblasts will be administered on day 0 only.; Other Names: COL7A1 gene-modified autologous fibroblasts

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Adverse events (AEs), Serious Adverse Events (SAEs), Adverse Reactions (ARs) and Serious Adverse Reactions (SARs) at each visit over 12 months' follow up period.	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Type VII collagen protein expression, measured by direct immunofluorescence, in the treated and untreated skin	Week 2, Month 3 and Month 12
Morphology of anchoring fibrils, measured by transmission electron microscopy, in the treated and untreated skin	Week 2, Month 3 and Month 12
Vector copy number, measured by q-PCR, in the treated and untreated skin	Week 2, Month 3 and Month 12
Anti-type VII collagen antibodies measured by ELISA and indirect immunofluorescence	Week 2, Month 1, Month 3, Month 6 and Month 12
T-cell responses to full length type VII collagen measured by ELISPOT	Week 2, Month 1, Month 3, Month 6 and Month 12

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: University College, London
• Investigators: Principal Investigator: John A McGrath, FRCP, King's College London

Publications and helpful links

General Publications

• Wong T, Gammon L, Liu L, Mellerio JE, Dopping-Hepenstal PJ, Pacy J, Elia G, Jeffery R, Leigh IM, Navsaria H, McGrath JA. Potential of fibroblast cell therapy for recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2008 Sep;128(9):2179-89. doi: 10.1038/jid.2008.78. Epub 2008 Apr 3.
• Lwin SM, Syed F, Di WL, Kadiyirire T, Liu L, Guy A, Petrova A, Abdul-Wahab A, Reid F, Phillips R, Elstad M, Georgiadis C, Aristodemou S, Lovell PA, McMillan JR, Mee J, Miskinyte S, Titeux M, Ozoemena L, Pramanik R, Serrano S, Rowles R, Maurin C, Orrin E, Martinez-Queipo M, Rashidghamat E, Tziotzios C, Onoufriadis A, Chen M, Chan L, Farzaneh F, Del Rio M, Tolar J, Bauer JW, Larcher F, Antoniou MN, Hovnanian A, Thrasher AJ, Mellerio JE, Qasim W, McGrath JA. Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa. JCI Insight. 2019 Jun 6;4(11):e126243. doi: 10.1172/jci.insight.126243. eCollection 2019 Jun 6.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2015
• Primary Completion (Actual): March 1, 2018
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: May 21, 2015
• First Submitted That Met QC Criteria: July 7, 2015
• First Posted (Estimate): July 10, 2015

Study Record Updates

• Last Update Posted (Actual): September 24, 2019
• Last Update Submitted That Met QC Criteria: September 20, 2019
• Last Verified: August 1, 2018

More Information

Terms related to this study

• 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: LENTICOL-F

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No