Introduction

The present invention relates to a promoter sequence for efficient expression of transgenes, particularly in immune cells, as well as to gene transfer vectors comprising said sequence for use in therapy. Primarily, it relates to lentiviral vectors that provide gene therapy for pathological conditions of the central nervous system (CNS), especially those characterized by neuroinflammation.

Technical features

Neuroinflammation, characterized by activation of microglial cells, plays an important role in the pathogenesis and progression of multiple diseases, such as lysosomal storage disorders and Alzheimer’s disease, serious human diseases currently lacking effective treatment.
This synthetic promoter aims to have minimal basal transcriptional activity and be highly inducible in the case of neuroinflammation. The new hHLA synthetic promoter can induce high expression of the transgene in vivo, in microglia myeloid cells derived from transplanted HSPCs (primary hematopoietic stem/progenitor cells), suggesting its ability to maintain the correct regulatory profile during differentiation of pluripotent cells into microglia cells, not being subject to epigenetic silencing or other undesirable forms of regulation.
The current level of technology development (TRL) has entered the preclinical stage.

Possible Applications

• Transgenic therapies for metachromatic leukodystrophy (MLD);
• Transgenic therapies for globoid cell leukodystrophy (GLD);
• Transgenic therapies for Alzheimer’s disease (AD);
• Transgenic therapies for amyotrophic lateral sclerosis (ALS);
• Transgenic therapies for Parkinson’s disease (PD);
• Transgenic therapies for multiple sclerosis (MS);
• Transgenic therapies for frontotemporal dementia (FTD);
• Transgenic therapies for GM1 gangliosidosis and GM2 gangliosidosis.

Advantages

• Promoter sequence capable of being produced at very high infectious titer;
• Promoter sequence capable of efficiently and safely transducing HSPC in vitro;
• Promoter sequence capable of transducing and driving a high level of transgene expression in vivo in long-term repopulated HSCs (hematopoietic stem cells);
• Promoter sequence of compact size, suitable for a lentiviral system.