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
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Safety of grafting SIN RV-mediated COL7A1 gene-modified autologous skin equivalent: Adverse Events (AE), Serious Adverse Events (SAEs), Adverse Reactions (ARs) and Serious Adverse Reactions (SARs)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Clinical and molecular diagnosis of RDEB with confirmed bi-allelic COL7A1 mutations
- •Reduced staining of C7 on skin biopsy, measured by immunofluorescence microscopy (IF)
- •A reduced number of/or morphologically abnormal anchoring fibrils confirmed by TEM
- •Detection of non-collagenous-1 domain (NC-1) of C7 on skin biopsy, measured by immunofluorescence microscopy (IF) and/or Western blot (WB) analysis
- •Presence of ≥100cm2 of blistered and/or erosive skin areas including chronic wounds suitable for skin grafting
- •Ability to undergo anaesthesia for skin grafting procedures
- •Subjects aged 18 years, willing and able to give informed consent
排除标准
- •Recipients of other investigational medicinal products within 6 months prior to enrolment into this study
- •Past medical history of biopsy proven skin malignancy
- •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
- •Known allergy to any of the constituents of the investigational medicinal product (IMP) including Penicillin
- •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
- •Positive results for HIV, Hepatitis BsAg, Hepatitis BcAb, Hepatitis C IgG, HTLV1&2 or Syphilis serology
- •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
- •Absence of adequate social support
- •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
研究组 & 干预措施
Autologous genetically modified tissue-engineered skin graft
Graft of SIN RV-mediated COL7A1 gene-modified autologous skin equivalent
干预措施: COL7A1-SIN retroviral vector engineered autologous tissue-engineered skin (Biological)
结局指标
主要结局
Safety of grafting SIN RV-mediated COL7A1 gene-modified autologous skin equivalent: Adverse Events (AE), Serious Adverse Events (SAEs), Adverse Reactions (ARs) and Serious Adverse Reactions (SARs)
时间窗: Month 12 post grafting.
The primary objective is to evaluate the safety of autologous autologous skin equivalent grafts genetically corrected with a SIN COL7A1 retroviral vector (RV) in adults with RDEB Primary Endpoints: Record of Adverse Events (AE), Serious Adverse Events (SAEs), Adverse Reactions (ARs) and Serious Adverse Reactions (SARs).
次要结局
- Changes in blister number over the grafted skin(Month 1, Month 2, Month 3, Month 6, Month 12 post grafting.)
- Change in instrument for Scoring Clinical Outcomes of Research for Epidermolysis Bullosa (iscorEB).(Month 1, Month 2, Month 3, Month 6, Month 12 post grafting.)
- Change in Quality of life: QOLEB questionnaire (Quality of Life for Epidermolysis Bullosa)(Month 1, Month 2, Month 3, Month 6, Month 12 post grafting.)
- Change in Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) - Activity(Month 1, Month 2, Month 3, Month 6, Month 12 post grafting.)
- Change in anchoring fibrils number(Month 1, Month 3, Month 6, Month 12 post grafting.)
- Change in scar quality: Vancouver Scar Scale (VSS)(Month 1, Month 2, Month 3, Month 6, Month 12 post grafting.)
- Change in Birmingham Epidermolysis Score (BEBS)(Month 1, Month 2, Month 3, Month 6, Month 12 post grafting.)
- Change in C7 protein expression(Month 1, Month 3, Month 6, Month 12 post grafting.)
- Changes in clinical appearance of grafted skin(Month 1, Month 2, Month 3, Month 6, Month 12 post grafting.)
- Changes in pruritus of grafted skin(Month 1, Month 2, Month 3, Month 6, Month 12 post grafting.)
- Evaluation of the humoral immune response against recombinant C7(Month 1, Month 6, Month 12 post grafting.)
- Change in Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) - Damage(Month 1, Month 2, Month 3, Month 6, Month 12 post grafting.)
- Evaluation of the cytotoxic immune response against recombinant C7(Month 1, Month 6, Month 12 post grafting.)