Introduction

This patent proposes a series of nucleotide sequences capable of promoting the expression of therapeutic genes, such as FVIII, in endothelial and hematopoietic cells for the treatment of hemophilia A. By limiting the expression of FVIII in specific cells, it allows to avoid the development of  inhibitors or the reduction of  pre-existing anti-FVIII antibodies, allowing the expression of the therapeutic gene, and therefore the long-term treatment of hemophilia A.

Technical features

Hemophilia A is a genetic disease that affects one male in every 5,000. Current therapy, which consists of frequent infusions of recombinant or plasma-derived FVIII, has drastically improved the quality of life of patients. However, infusions do not offer a definitive cure, as FVIII has a short half-life in the bloodstream, it’s an expensive procedure and constant infusions can lead to the expression of antibodies inhibiting the activity of infused FVIII in about 30% of critical patients. The patented nucleotide sequences, on the other hand, allows for the selective expression of FVIII in endothelial and hematopoietic cells, in percentages higher than 25% in a preclinical model of hemophilia A, where a 2% expression is sufficient to improve a patient’s quality of life. In addition, the FVIII is expressed for a long time (one year) and the selectivity of the sequences does not promote the expression of antibodies or, if these are pre-existing, reduces / eliminates their presence following gene therapy.

 

Possible Applications

• Gene and cellular therapy for Heamophilia A;
• Regulated expression of recombinant and/or therapeutic proteins in specific cells.

Advantages

• The identified nucleotide sequences are selective for endothelial and hematopoietic cells;
• FVIII expressed for a long time;
• No expression of anti-FVIII antibodies;
• The therapy is also active in the presence of anti-FVIII antibodies which tend to decrease/be eliminated following treatment.