Technology

Viral vectors have become one of the leading gene delivery systems for genetic medicine in humans. However, multiple gene therapy assets have encountered challenges with their local and safe delivery. At EG 427, we have created a unique approach, utilizing a recombinant non-replicative HSV-1 vector, to provide clinicians with a precision gene therapy solution to treat chronic diseases.

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Our unique aproach

Our unique & versatile vectors are characterized by their ability to provide:

Large capacity. The modified vector can carry a larger genetic payload, of over 30kb, than most other viral vectors (e.g. adeno-associated viruses). The possibility to deliver more in one go enables the inclusion of regulatory sequences to finely tune gene expression, as well as the full genetic instructions for building large or multiple therapeutic proteins.

Life-long relationship with the host. HSV-1 and humankind have co-evolved to reach a balanced interaction. Even with a history of HSV-1 infection, attenuated and non-replicative HSV-1 vectors have been clinically proven to allow transgene expression without significant immune response or reactivation of latent wild-type HSV-1, even when multiple redosing is implemented. Moreover, HSV-1 does not integrate within the host DNA, hence preserving the patient’s genome integrity.

Target selectivity. HSV-1 infects cells by binding to host receptors using its membrane-embedded proteins that can be easily engineered for selective delivery in new therapeutic indications.

Wild-type HSV

Infection with a herpes simplex virus type 1 (HSV-1) is very common globally. It’s estimated that around 3.7 billion people, 2/3 of the world’s population between the ages of 0 and 49 are infected, although many people never develop symptoms. Once infected, an individual carries the HSV-1 genome for the rest of their life, as it establishes lifelong dormant (‘latent’) infection in the host’s peripheral neurons. During latency, the HSV-1 genome is maintained as an episome, which undergoes only limited gene expression. At EG 427, we used this ability of HSV-1 to establish latency in developing our innovative and powerful therapeutic approach.

Non-Replicative HSV

HSV-1 genes can be divided into three groups based on their time of expression: 'immediate early', 'early' and 'late'. Deletion, or inactivation, of immediate early genes prevents the expression of all other viral genes, thus disabling viral replication. These precision deletions are at the heart of our approach to convert HSV-1 into a safe and efficient non-replicative gene therapy vector, which we call nrHSV-1. Moreover, such truncations of the viral DNA make available genomic space within the icosahedral capsid to carry large (over 30kb) genetic cargo.

In the latent state, the Latency-Associated Transcripts (LAT) region remains transcriptionally active, allowing long-term expression of transgene(s) inserted within this region. This is a component of our approach that is fundamental for the treatment of chronic diseases.

Scientists have also demonstrated that the administration of nrHSV-1 does not result in reactivation or recombination events with latent wild-type HSV-1, thus ensuring an excellent safety profile even with a highly prevalent human virus (see white paper). 

Manufacturing

Addressing more widespread, chronic, diseases requires highly efficient manufacturing processes. Associated with our nrHSV-1 platform, we have developed broad expertise and know-how in the manufacturing of our vectors. This includes using unique producer cell lines to address manufacturing productivity and quality challenges. These vital production tools provide the missing viral genes to allow vector production using simple and efficient infection process in our bioreactors. Engineering, maintenance, and improvement, of these cell lines requires considerable technical expertise, which we have in-house.

Our manufacturing processes, both upstream and downstream, have been developed up to GMP-grade, using fully scalable bioreactor processes.

Research

By further engineering our vector platform to change the tropism towards other tissue types, we are expanding the platform’s capabilities to address unmet clinical need in a growing array of indications beyond PNS. These include CNS neurons, and other non-replicative, or slowly replicative, cell types. 

Based on this versatility of our platform, we are exploring, alone and through our collaborations, different localized, chronic indications.

As product and process are tightly linked, we keep pushing the limits of the manufacturing yields that can be achieved, to deliver lower cost of goods.

Publications and White papers

HSV-1’s contribution as a vector for gene therapy
2022
HSV-1’s contribution as a vector for gene therapy

Test. An outstanding feature of HSV-1 vectors is a possibility of delivering over 30 kbp of genetic cargo to the nucleus of human cell with no toxicity and low immunogenicity

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Development and Assessment of  (HSV-1) Amplicon Vectors with Sensory Neuron-Selective Promoters
2022
Development and Assessment of (HSV-1) Amplicon Vectors with Sensory Neuron-Selective Promoters

The aim of this study was to develop and assess tools for the characterization of sensory neuron-specific promoters in dorsal root ganglia (DRG) neurons after transduction with herpes simplex virus type 1 (HSV-1)-based amplicon defective vectors.

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Acute Intravesical Capsaicin for the Study of TRPV1 in the Lower Urinary Tract: Clinical Relevance and Potential for Innovation
2022
Acute Intravesical Capsaicin for the Study of TRPV1 in the Lower Urinary Tract: Clinical Relevance and Potential for Innovation

Capsaicin acts on sensory nerves via vanilloid receptors. TRPV1 has been extensively studied with respect to functional lower urinary tract (LUT) conditions in rodents and humans.

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Absence of reactivation or of mobilization of HSV-1 genomes following infection of the non-replicative HSV-1 vector for gene therapy
2022
Absence of reactivation or of mobilization of HSV-1 genomes following infection of the non-replicative HSV-1 vector for gene therapy

Wild type Herpes Simplex Virus type 1 (HSV-1) is a very common virus. Using non-replicative vectors derived from HSV-1 for gene therapy approaches thus requires that neither reactivation of, nor recombination with preexisting infection occurs after administration of such therapy. 

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