Nucleic Acid Agents Targeting CHiLL1 and CHiLL2 for NSCLC
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Solution Overview
Problem
Current treatments for non-small-cell lung cancer (NSCLC), particularly those with KRAS mutations, face challenges due to rapid development of resistance and limited therapeutic options, with existing targeted therapies only effective for a minority of patients and cytotoxic chemotherapeutics offering poor long-term survival rates.
Innovation Solution
Development of nucleic acid agents targeting specific long non-coding RNAs (lncRNAs) such as CHiLL1 and CHiLL2, which are combined with platinum anticancer drugs to inhibit cancer cell proliferation and chemoresistance, using antisense oligonucleotides and CRISPR-Cas technology for effective perturbation and downregulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If targeted small-molecule therapies are used for EGFR and ALK mutations, then treatment effectiveness is improved for minority patients, but applicability is limited to only 15-3% of patients
Solution Approach 1:
The patent develops a pooled CRISPR screen platform that can universally screen multiple lncRNA targets across different NSCLC patient populations, making the screening method applicable to all NSCLC patients regardless of specific mutation type, thereby achieving universality while maintaining effectiveness
2Adaptability or versatility
If cytotoxic platinum-based chemotherapeutics are used, then treatment coverage is expanded to majority of patients including KRAS-mutated cases, but resistance develops rapidly and long-term survival remains poor
Solution Approach 1:
The patent performs preliminary CRISPR screening to identify lncRNAs that confer chemoresistance before chemotherapy treatment, enabling selection of patients who will respond to platinum-based therapy and identifying those who will develop resistance, allowing for preliminary intervention strategies
Solution Approach 2:
The patent uses CRISPR screening results as feedback to identify resistance mechanisms and select optimal treatment combinations, creating a feedback loop where screening data informs treatment decisions to improve long-term survival outcomes
3Adaptability or versatility
If lncRNAs are used as therapeutic targets, then personalized therapy potential is improved with low side effects, but screening sensitivity is reduced due to insensitivity to RNAi perturbation
Solution Approach 1:
The patent replaces RNAi-based screening (which relies on RNA interference mechanisms) with CRISPR-Cas9-based screening (which uses programmable DNA targeting and Cas9 nuclease activity), substituting one molecular mechanism for another that is more effective at detecting lncRNA function
4Reliability
If CRISPR-Cas technology is used for lncRNA perturbation, then screening effectiveness is improved, but technical complexity increases compared to traditional RNAi methods
Solution Approach 1:
The patent segments the CRISPR screening process into modular components: pooled sgRNA library construction, transfection protocols, phenotypic screening assays, and data analysis pipelines, making the complex technology more manageable and implementable
Data Source
AI summary
One aspect of the invention relates to a nucleic acid agent targeting a long non-coding RNA target selected from ENSG00000253616 (CHiLL1; SEQ ID NO 001) and ENSG00000272808 (CHiLL2; SEQ ID NO 002) for use in treatment or prevention of recurrence of non-small-cell lung cancer.In another aspect, the invention relates to a pharmaceutical composition comprising a first nucleic acid agent targeting CHiLL1 and a second nucleic acid agent targeting CHiLL2.Particular embodiments provide for the agents and compositions provided in treatment of cancers characterized by KRAS activating mutations, and/or drug resistance. Other particular embodiments provide their combination with platinum anticancer drugs.