Innovative RNA Therapeutics for Combatting RNA Viruses

Background

Dengue virus (DENV) infection, caused by one of the four serotypes of the virus transmitted primarily by Aedes mosquitoes, poses significant global health challenges. Despite its widespread prevalence, particularly in tropical and subtropical regions, several critical unmet needs persist in the clinical and therapeutic management of dengue

There are currently no FDA-approved antiviral drugs specifically for the treatment of dengue. While supportive care remains the standard treatment, specific antivirals that can effectively inhibit the virus and reduce the duration and severity of symptoms are urgently needed

Vaccines that are safe and effective for individuals regardless of their previous infection status, including those who are seronegative, and that provide balanced protection against all four dengue virus serotypes.

Technology Overview

Defective interfering (DI) RNA has been described almost 80 years ago. They are natural products of viral replication – formed due to errors (deletion and recombination) during viral RNA replication.These errors lead to incomplete or shortened copies of the viral genome, which lack genes necessary for viral replication. However, they can disrupt replication of parental virus through:

• Compete for resources -enzymes and nucleotide
• Act as a template for RNA synthesis
• DENV RNA pol replicated DI RNA
• Compete for packaging and assembly, leading to DIP
• Viral particles that contain defective genomes can not multiply on their own- need helper virus to replicate and to be packaged into DI particles

DI RNA activates innate immune response and triggers antiviral response in cells.

The main safety concern is that treating with DI RNA can induce IFN responses leading to a “cytokine storm” event. DIPs and DI RNA therapy activates innate immune responses but no data indicates therapy leads to a cytokine storm event. DIPs are inherently safe as they are non-replicating unless viral infection is present.

DI290 RNA can be used to treat Dengue Fever:

• Delivered by DIP or LNP
• Direct competition for viral and cellular resources; activate cellular antiviral responses
• Intraperitoneal, but nasal and oral delivery possible
• Positioned to be first-in-class with continued success

Stage of Development

LNP-DI290 treatment in IFNAR KO Mice

Benefits

• The Dengue Fever Market is expected to garner a market value of US$ 877.82M in 2023 and incidence is increasing due to climate change
• The majority of cases are reported from Brazil (2,182,229), Vietnam (325 604), Philippines (201,509), India (110,473), and Indonesia (94,355)
• Large pharma has significant presence in the therapeutic area – with vaccines: Sanofi, Takeda, Merck and LMWs: Novartis, Janssen
• Only one early stage RNA competitor - Meletios Therapeutics

Opportunity

The Research Institute is searching for partners throughout the development path:

• Optimisation of non-GMP production scale-up for preclinical development
• Optimise oral formulation (ongoing)
• Perform H2H benchmarking with advanced LMW candidates to demonstrate superiority in vitro and in vivo – advantage may be efficacy, safety or manufacturability
• Elaboration of MoA
• Exploratory PK/PD studies, dosing, distribution and toxicology studies
• Considerations for CMC – GMP-grade cell line (including viral vectors) required
• IND-enabling studies and define clinical strategy