Systemic Collagen VII Replacement Therapy for Advanced Recessive Dystrophic Epidermolysis Bullosa

Area of Science:

• Genetics
• Dermatology
• Biochemistry

Background:

• Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic skin disorder caused by COL7A1 mutations, leading to collagen VII (C7) deficiency and multiorgan fibrosis.
• Collagen VII (C7) is crucial for skin integrity and regulates scarring and TGFβ bioavailability.
• Previous studies showed intravenous recombinant C7 (rC7) rescues neonatal RDEB mice, but its efficacy in established adult RDEB was unknown.

Purpose of the Study:

• To investigate the therapeutic potential of intravenous rC7 in established adult RDEB animal models.
• To assess the impact of rC7 on fibrosis, TGFβ signaling, and skin integrity in RDEB.
• To evaluate the safety and tolerability of repeated IV rC7 administration.

Main Methods:

• Utilized small (mice) and large (dogs) adult RDEB animal models.
• Administered rC7 intravenously (IV) and assessed its distribution and effects over 7 weeks.
• Measured fibrosis, TGFβ signaling, wound healing, and dermal-epidermal separation.

Main Results:

• IV rC7 accumulated at the basement membrane zone in multiple organs after a single infusion in RDEB mice.
• Repeated IV rC7 injections significantly reduced skin and eye fibrosis in adult RDEB mice, correlating with decreased TGFβ signaling.
• In RDEB dogs, IV rC7 integrated into the dermal-epidermal junction, improving wound healing and reducing tissue separation.

Conclusions:

• Repeated intravenous administration of rC7 demonstrates disease-modulating effects in established adult RDEB models.
• rC7 treatment reduced fibrosis and improved skin integrity, indicating its potential as a systemic therapy for RDEB.
• IV rC7 was well-tolerated in both RDEB mouse and dog models, supporting its clinical applicability.