Awarded a one-year, $88,200 grant from Pachyonychia Congenita Project.
The main problem of patients with PC is the intense pain they feel when walking. This is due to the malfunction of some skin-forming proteins, especially in the soles of the feet. This malfunction is due to errors (mutations) in the instructions carried by the genes encoding these proteins. Our project is based on correcting these errors directly in the skin of the patients so that the proteins function correctly again and thus mitigate the pain that patients suffer when walking. To achieve this, we will design tools to cut at the DNA location of the genetic defect using a kind of molecular scissors
called CRISPR. Once the erroneous DNA has been cut out, we will be able to remove the disease-causing DNA copy to recover the precise instructions needed for the proteins to function normally again. We will test various methods to find the most effective way to introduce these molecular scissors directly into patients’ skin cells so that they can perform their functions most effectively, resulting in a “genetic cream” that reduces or eliminates the symptoms of the disease.
Project Title : Personalized preclinical gene editing protocols for the in vivo correction of Pachyonychia Congenita.
Principal Investigator (PI) Name : Marta Garcia Diez, PhD
PI Affiliations : UC3M-CIEMAT
Abstract
It is possible to develop treatments for Pachyonychia Congenita based on gene editing techniques to reduce the pathological thickening of the plantar epidermis that causes pain and disability in these patients. These treatments could constitute a long-lasting curative therapy that could improve the patient’s quality of life. CRISPR-mediated gene editing will permit mutation-specific pathogenic allele inactivation in patient epidermis in vivo allowing for the disease phenotype to be mitigated by recovering the intermediate filament cytoskeleton in a fraction of keratinocytes. Our goal is to develop in vivo treatment protocols for therapeutic benefit in the pathology of plantar keratoderma, focusing on viral (third generation adenoviral) and non-viral (magnetofection for CRISPR RNPs for CRISPR-encoding mRNAs). We will investigate the long-term maintenance of gene-edited epidermal stem cells, potentially enabling lifelong mitigation of the pathology in PC patients.The comparison of the efficacy of viral and non-viral vectors to administer the CRISPR system in the skin in vivo, as well as the biosafety evaluation of these tools, will allow the design of preclinical protocols to advance towards the clinical use of gene-editing therapy with CRISPR in this pathology.
