Restoration of Full-Length Type VII Collagen in RDEB Patients With Nonsense Mutations After Intravenous Gentamicin Treatment
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Generation of anchoring fibrils
研究概览
简要总结
Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable, devastating, inherited skin disease caused by mutations in the COL7A1 gene that encodes for type VII collagen (C7), the major component of anchoring fibrils (AFs), structures that mediate epidermal-dermal adherence. Thirty percent of RDEB patients have nonsense mutations. The investigators recently demonstrated in 5 such patients that intradermal and topical gentamicin induced "read-through" of their nonsense mutations and created robust and sustained new C7 and AFs at the dermal-epidermal junction (DEJ) of their skin and also stimulated wound closure and reduced new blister formation. No untoward side effects occurred. Herein, the investigators propose evaluating the safety and efficacy of intravenous gentamicin in these patients. In theory, this intravenous administration has the possibility of treating simultaneously all of the patients' skin wounds. The milestones will be increased C7 and AFs in the patients' DEJ, improved EB Disease Activity Scores, and absence of gentamicin side effects.
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
- 7 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of signed and dated informed consent form
- •Stated willingness to comply with all study procedures and availability for the duration of the study
- •Male or female, aged 7 and up can participate in the 14 day IV gentamicin trial. Male or female, aged 18 and up can participate in the 3 month IV gentamicin trial.
- •Been diagnosed with recessive dystrophic epidermolysis bullosa (RDEB) and with a nonsense mutation in the COL7A1 gene.
- •Immunofluorescence evaluation of skin biopsies reveals absence or decreased intensity of C7 expression at their DEJ (dermal epidermal junction) compared with normal human skin biopsies.
- •Cultured fibroblasts from patient skin synthesize and secrete full-length, 290kDa C7 alpha chains in the presence of supplemented gentamicin (400 μg/ml in culture).
- •Ability to sit or lie down for over 30 minutes for IV infusions. For those in the 3 month trial, to be willing to continue treatment at home under the supervision of licensed and trained infusion nurses.
排除标准
- •Recent exposure to gentamicin within the past 6 weeks.
- •Pre-existing known auditory impairment.
- •Pre-existing known renal impairment.
- •Pre-existing known allergies to aminoglycosides or sulfate compounds.
- •Pregnancy or lactation
- •Current use of medications with known ototoxicity or nephrotoxicity.
- •Current enrollment in another experimental clinical trial involving systemic treatment with C7 or C7 producing products for the treatment of RDEB.
研究组 & 干预措施
Intravenous Gentamicin
Intravenous gentamicin (7.5 mgs/kg) daily for for either 14 days and then stopped or twice weekly for three months and then stopped.
干预措施: Gentamicin (Drug)
结局指标
主要结局
Generation of anchoring fibrils
时间窗: 6 months
Generation of new anchoring fibrils as assessed by immuno-electron microscopy
Full-length type VII collagen expression
时间窗: 6 months
Increased expression of full-length type VII collagen as assessed by immunofluorescence
Absence of gentamicin side effects
时间窗: 6 months
Absence of gentamicin side effects, especially the detection of any ototoxicity or nephrotoxicity
次要结局
- Improved Quality of Life score(6 months)
- Improved Disease Activity scores(6 months)
研究者
David Woodley
Professor
University of Southern California