Project Details
Description
Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a prototypical genodermatosis caused by biallelic loss-
of-function mutations of COL7A1. These mutations lead to a lack of type VII collagen (C7) in the skin and
mucosal membranes, resulting in a complex phenotype of blistering, fibrosis, pseudosyndactyly, joint
contractures, esophageal strictures, corneal abrasions, malnutrition, autoimmunity, anemia, and squamous cell
carcinoma. Despite tremendous efforts over the last decade to establish curative measures for this severe and
potentially fatal disorder, there are as yet no therapies that reliably supply C7 protein to the multiple sites
affected by generalized severe RDEB. To address this, we propose to gain a more mechanistic understanding of
how to restore the integrity of COL7A1 without causing collateral damage to the rest of the genome, and of how
the specialized tropism of cells works to deliver intact, functional C7 throughout the body. In order to
accomplish these goals and to overcome the limitations of current gene and cell therapies, we will investigate
the following questions: [i] Is base editing superior to CRISPR/Cas9-editing for correction of COL7A1
mutations? Because base editing does not cause double-strand breaks in the way that classic gene editing with
DNA nucleases does, it avoids genotoxic stress. [ii] Are skin-specialized cells, such as ABCB5+ mesenchymal
stromal/stem cells (MSCs), superior to alternative sources of MSCs in expression of C7 levels adequate for
cross-correction of C7 deficiency in RDEB? We will evaluate skin-specific stromal cells, such as mesenchymal
stromal cells expressing ATP-binding cassette sub-family B member 5 (ABCB5+) surface protein, derived
directly from skin or indirectly from patient-specific induced pluripotent stem cells, which have had COL7A1
restored to function with base editing. [iii] Do COL7A1-edited human ABCB5+ MSCs mediate wound healing in
a preclinical murine model of RDEB? Using our murine model of RDEB that accepts human xenografts, we will
quantify the value of base editing-corrected ABCB5+ MSCs and induced pluripotent stem cell-derived MSCs.
We propose to define the conditions conducive to wound healing in this severe blistering genodermatosis by
using powerful tools for studying and manipulating the information bases of biological systems (i.e.,
programmable deaminases for base editing-mediated gene therapy; induced cell lineage conversion; and skin
tropism). We will aim for personalized cell therapy for individuals with generalized severe RDEB, with the idea
that our findings may provide insights into ways to manage other genodermatoses, as well as treatment of
mucocutaneous ulcers, and chemical and thermal burns. Our proposal is equally motived by wanting a better
understanding of the biological mechanisms in injured skin and by needing to improve the lives of people with
RDEB through reducing the risks and maximizing the benefits of potential novel gene and cell therapies.
Status | Active |
---|---|
Effective start/end date | 4/1/13 → 8/31/24 |
Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $435,018.00
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $435,018.00
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $330,770.00
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $435,018.00
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $341,000.00
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $337,590.00
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $437,074.00
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $458,962.00
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $339,167.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.