Technology and Innovation

Riboswitch In-vivo Delivery Platform:

Precise in-vivo Production of Therapeutic Proteins and Peptides Using Oral Small Molecule Inducers

Our proprietary riboswitch technology provides exquisite control of mRNA production from any DNA template using bespoke oral small molecules – allowing precise control of the timing and level of in-vivo production of therapeutic proteins:

 

 

Mechanism of action:

Our rationally designed synthetic riboswitches are incorporated into the coding sequence of any activate transgene expression via a splicing based expression platform cassette.

In the absence of the inducer (‘OFF’ state), inclusion of an alternative exon containing a premature stop codon drives immediate degradation of the mRNA via the ubiquitous process of nonsense-mediated decay. Thus, in the absence of the small molecule inducer, no protein is expressed.

When the small molecule inducer is present (‘ON’ state), specific binding of the inducer to the riboswitch aptamer drives stabilization of a hairpin structure and blocking of the 5’ splice site – resulting in splicing out of the entire regulation cassette, formation of a stable mRNA transcript, and protein expression.

An innovative approach for in-vivo delivery of therapeutic proteins and peptides

Our riboswitch gene regulation system provides a novel approach for in-vivo delivery of any therapeutic protein, unlocking the potential of genetic medicine for treatment of a wide range of prevalent disorders.

We have demonstrated in-vivo efficacy across multiple targets (vectorized antibodies, peptides, hormones, cell-surface receptors and nucleases) and therapeutic modalities (gene therapy, gene editing, and cell therapy).

In-vivo delivery of native metabolic proteins & peptides:

• When applied to different combinations of vectorized native peptides, myokines and adipokines, our riboswitch in-vivo delivery platform provides the solution to many of the current issues associated with injectable peptides or oral drugs, with important implications for delivery, manufacturing access and cost.
• In preclinical models, we have demonstrated remarkable improvements in efficacy and safety upon delivery of wild-type, short lived gut peptide combinations, and have demonstrated the impact of delivering adipokines and myokines on prevention of fat regain and muscle maintenance.

Cell Therapy:

• MeiraGTx has applied riboswitch technology to control CAR and cell fate determining factors with an oral small molecule.
• In CAR-T, we have demonstrated that the riboswitch control of CAR expression leads to significant improvements in efficacy and safety, including maintaining naïve T-cell phenotype, elimination of exhaustion markers, durable proliferation, 4-fold increase in in-vitro cytotoxicity and a 3-fold improvement in in-vivo potency when compared to the currently approved CD19 CAR-T as well as other CARs for solid tumors.

Vectorized antibodies:

• Riboswitch allows precise in-vivo expression of vectorized antibodies, with the ability to activate expression of antibodies systemically, or in the CNS using BBB-crossing inducers.
• We have demonstrated the modularity of our riboswitch platform for in-vivo delivery of antibodies across many commercially approved therapeutic antibodies.

Gene Editing:

• Riboswitch allows tight control of DNA or RNA editors to avoid off-target editing, immunogenicity, and improve editing efficiency.