taking advantage of the HSV-1 virus
Viruses are infectious agents that have evolved to efficiently enter specific host cells where they deploy their genetic material - either DNA or RNA - and utilize the host machinery to replicate. Because of their unique biology, viruses gained an interest as vehicles that could be engineered to deliver therapeutic DNA or RNA sequences to cells for the purpose of gene therapy. While several types of viruses have been engineered to support gene therapy, herpes simplex virus type 1 (HSV-1) presents a number of key natural features that should allow to extend the benefits of gene therapy to more patients and indications.
HSV-1 is a human, enveloped virus that naturally infects epithelial cells of the skin or mucosa, before reaching nerve cells: it is said to be neurotropic. Once inside a peripheral neuron, the virus enters into latency, a state in which it can lie dormant for a lifetime. HSV-1 is extremely common and afflicts billions of humans around the globe, with a prevalence of 65% to 90%, depending on the country [Wald, A. et al.].
Importantly, the virus presents limited pathogenesis, occasionally reactivating to cause benign fever blisters and rarely leading to severe complications. Instead, recurrent HSV-1 infections most often remain subclinical, arguing for a positive safety profile of the virus as a therapeutic tool.
The HSV1 Virus
In terms of gene delivery and expression, HSV-1 presents a number of advantages with respect to other viral vectors. Most importantly, it is a large virus with a 153-kb linear DNA genome that can carry complex therapeutic constructs of over 30 kb in length. It can therefore accommodate not only single or multiple large transgenes, but also complex promoters and regulatory elements to tightly and physiologically control their expression. In addition, the latent viral genome supports expression of the transgene in the long term when it is inserted within its LAT locus (Latency Associated Transcript locus), even though it does not integrate into cellular chromosomes, thus avoiding the risk of insertional mutagenesis. Furthermore, the vector is amenable to repeat dosing when required.
Comparison of Viral Gene Therapy Vectors
LV: Lentivirus; AAV: Adeno-Associated Virus; AdV: Adenovirus
1/ Possibility of carrying out a pharmacological follow-up of the virus by in vivo assays;
2/ Level of neutralizing antibodies above exclusion criteria;
3/ Linked to the level of humoral immune response to the viral vector.
Because HSV-1 is a neurotropic virus that establishes a natural latent state in peripheral neurons, diseases of the peripheral nervous system (PNS) appeared as the best suited indications for which HSV-1-based gene therapy would be particularly appropriate.
What Our scientific founder says
The biology of the HSV-1 virus naturally drives infection towards peripheral neurons, one of the many unique characteristics of this virus. We are taking this property to our advantage, using HSV-1-based gene therapy vectors to naturally target diseases that affect the peripheral nervous system, with the first on our list being neurogenic bladder.
Charles Joussain, MD, PhD
Post-doctoral position as visiting researcher at King's College London
University of Versailles Saint-Quentin, Paris-Saclay, France