Ex Vivo Gene Therapy Clinical Trial for RDEB Using Genetically Corrected Autologous Skin Equivalent Grafts

Phase I/II ex Vivo Gene Therapy Clinical Trial for RDEB Using Autologous Skin Equivalent Grafts Genetically Corrected With a COL7A1-encoding SIN Retroviral Vector

This phase I/II clinical trial aims to treat 3 adult subjects with Recessive Dystrophic Epidermolysis Bullosa, expressing residual C7 levels, by genetically corrected autologous skin equivalent grafts on selected areas (up to 300 cm2).

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a severe orphan genetic disease responsible for skin and mucosal detachments due to a loss of adhesion of the epidermis to the underlying dermis. The disease is caused by loss of function mutations of the COL7A1 encoding type VII collagen (C7) which forms anchoring fibers, which are essential structures for dermal-epidermal adherence. Current treatments are only symptomatic and do not effectively treat or prevent the occurrence of cutaneous and mucosal detachments responsible for local and systemic complications that threaten the vital prognosis.

EBGRAFT is a prospective open-label international monocentric phase I/II clinical trial. It aims to treat 3 adult subjects with RDEB, expressing residual C7 levels, by genetically corrected autologous skin equivalent grafts.

The skin equivalent consists of keratinocytes and fibroblasts from the patient, genetically corrected ex vivo with a secure Self INactivating (SIN) retroviral vector expressing the COL7A1 cDNA under the control of the ubiquitous human promoter EF1a.

Each patient will be grafted sequentially at Necker Hospital in Paris using autologous genetically corrected skin equivalents of approximately 300 cm2 (up to 6 grafts of 50 cm2 each).

The main objective is to evaluate the safety of autologous skin equivalent grafts genetically corrected with a SIN COL7A1 retroviral vector (RV) in adults with RDEB.

The secondary objectives are:

1. To evaluate the efficacy of transplanting autologous skin equivalent genetically corrected with RV SIN COL7A1 in adults with RDEB.
2. To evaluate the immune response against recombinant type VII collagen (C7).

This clinical trial should evaluate whether the grafting of these genetically corrected autologous skin equivalents is well tolerated and whether they restore normal dermal-epidermal adherence of the grafted areas. The proposed treatment aims to obtain a permanent correction of the grafted areas, allowing skin healing and reducing pain. It has the potential to reduce itching, to prevent the occurrence of blisters and skin detachments, reduce the risk of infections, the duration and cost of care and also the risk of development of squamous cell carcinomas in the grafted areas.

Inclusion Criteria:

1. Clinical and molecular diagnosis of RDEB with confirmed bi-allelic COL7A1 mutations
2. Reduced staining of C7 on skin biopsy, measured by immunofluorescence microscopy (IF)
3. A reduced number of/or morphologically abnormal anchoring fibrils confirmed by TEM
4. Detection of non-collagenous-1 domain (NC-1) of C7 on skin biopsy, measured by immunofluorescence microscopy (IF) and/or Western blot (WB) analysis
5. Presence of ≥100cm2 of blistered and/or erosive skin areas including chronic wounds suitable for skin grafting
6. Ability to undergo anaesthesia for skin grafting procedures
7. Subjects aged 18 years, willing and able to give informed consent

Exclusion Criteria:

1. Recipients of other investigational medicinal products within 6 months prior to enrolment into this study

2. Past medical history of biopsy proven skin malignancy

3. 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) including Penicillin

5. Subjects with BOTH:

   • positive serum antibodies to C7 confirmed by ELISA and
   • positive IIF with binding to the base of salt split skin and/or
   • positive Western blot

6. Positive results for HIV, Hepatitis BsAg, Hepatitis BcAb, Hepatitis C IgG, HTLV1&2 or Syphilis serology

7. Clinically significant medical, psychological or laboratory abnormalities limiting the ability of the subject to travel to the trial site(s) and to undergo grafting and follow-up procedures, as determined by the Investigator

8. Absence of adequate social support

9. Subjects who are pregnant, breast-feeding or of child-bearing potential who are neither abstinent nor practicing 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 the duration of the trial