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ARTAN Bio - Mutation-Specific Codon Suppression for Aging and Longevity


Stage
Early stage preclinical discovery
Area
Drug development
Status
Ongoing
Patent Status
Not filed yet
Background
Nonsense mutations, alterations in the DNA or RNA sequence that produce a premature termination codon (PTC), result in the production of incomplete, nonfunctional proteins. These mutations have profound implications, being associated with roughly 10% of genetic diseases, such as cystic fibrosis.The accumulation of nonsense mutations have been implicated in age-related diseases like cancer and Alzheimer's. Particularly common is the mutation that changes a CGA codon into an opal-stop codon.. To combat the negative effects of these mutations, several strategies have been employed. These include the inhibition of Nonsense-Mediated mRNA Decay (NMD) using drugs and the process of pseudouridylation. While these methods have shown some success, they are not without drawbacks, including potential low efficiency and the risk of creating aberrant proteins.
Aims, Hypothesis & Results
Aim:
To engineer and validate a nonsense suppression system that can effectively and specifically target nonsense codons without competing with normal tRNA, aiming to restore proper protein translation in genes affected by these mutations.
Hypothesis:
An bio-inspired nonsense suppression system can recognize the premature stop codon introduced by nonsense mutations n and replace it with its correct amino acid. This action would restore normal protein translation without significantly impacting natural termination codons or generating aberrant proteins.
Result (Preliminary):
Initial ribosome profiling data from experiments using a cancer cell line, which has anonsense mutation in a tumor suppressor gene, indicates that the nonsense suppression system can effectively restore protein levels. The nonsense suppression system demonstrated better specificity compared to existing interventions like G418, as it did not show significant read-through at natural termination codons. Furthermore, AAV was identified as a promising vector for delivering the nonsense suppression system, given its efficiency in transducing various tissues and its previous clinical successes.
Timeline
Milestone 1 – Start of the project - project kickoff meeting after on-chain approval of the proposal.
Phase 1 : Design & generate a nonsense suppression construct for use in an AAV vector.
Milestone 2 – Go / no go check – Completion of phase 1 and presentation of results in a dedicated meeting or at a quarterly review.
Phase 2 : In vitro testing of selected vectors/oligos.
Milestone 3 – End of the project - Completion of phase 2 and presentation of results in a dedicated meeting or at a quarterly review, proposal for next round of funding. Note, a provisional patent could be filed at this stage.
Required Funding: $ 91,300
Status: Ongoing
Duration: 6 Months
VitaDAO Board Evaluation Writeup
The emerging nonsense suppression therapeutic strategy offers a promising approach to suppress nonsense mutations.. Led by a seasoned drug developer, preliminary results show potential in rescuing vital tumor-suppressor genes, providing a versatile "pipeline in a pill" solution due to its shared mechanism across diseases. Its compact payload size further streamlines delivery, addressing a nuanced aspect of aging. However, the approach treads on uncharted grounds, presenting challenges like potential toxicity, delivery issues, and uncertainties in biology that might yield off-target effects.

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