Dave Keng Boon WEE

RNA Modulations for Novel Therapeutics
PhD – Computational Systems Biology, National University of Singapore (NUS)

SUMMARY
Dave majored in chemical engineering at the National University of Singapore (NUS), during which he also self-learnt computer science and programming. In 2000, right upon graduation, he co-founded a startup providing computing platforms for consumers and businesses to access their applications and data from any computer via the Internet, a concept now known as cloud computing; the Internet at its nascent stage required him to develop the underlying technology from stretch. The concept was a decade too early as the inadequate and costly Internet bandwidth infrastructure became an insurmountable barrier to gain market traction. Subsequently, he joined a subsidiary of ST Technologies Ltd as a software lead to develop and commission a real-time command-and-control artillery system for the SAF. Still hungry for startups and sensing potential market opportunity from an emerging bioinformatics field, he seized on the inaugural scholarship offered by the Bioinformatics Institute to pursue a M.Sc. in bioinformatics, during which he received the Outstanding Research for Young Scientist award by the Human Genome Organization (HUGO), and thereafter, attained a Ph.D. in computational systems biology under an A*STAR scholarship in 2009, both at NUS. He joined the Institute of High Performance Computing and was awarded an Independent Investigatorship in 2008. He then went on to become a Group Leader and subsequently Principal Investigator at the Institute of Molecular and Cell Biology, leading the RNA Modulation for Novel Therapeutics Lab. He is also a Cluster Chair for the National Initiative of RNA Biology and Applications (NIRBA), which aims to better understand the basic biology of RNA.

Dave derives immense satisfaction from inventing technologies that powers the advancement of science and industry. He is especially captivated by complex dynamical systems and with his engineering mindset, he is obsessed with the perturbation of such systems in a rationally manner for one’s desired goals. As a fan of “you can’t engineer something you don’t understand”, his approaches are based on mechanistic or first-principle modelling and systems analyses. To provide the agility and flexibility to work on myriad research areas, he collaborates extensively with wet experimentalists to validate his hypotheses and predictions. As of 2018, his technologies have been used in more than 50 projects in 28 labs from 24 local and international research institutions and the biopharmaceutical industry. Part of his work was commercialized in 2018 when he co-founded ImmuNOA Pte Ltd, an A*STAR spin-off that develops and applies innovative therapeutic modalities leading to transformative cell immunotherapies. ImmuNOA was acquired by LionTCR Pte Ltd, a leading cell therapy company in Singapore in 2024.

AWARDS & GRANTS

AWARDS

  • 2012: IHPC Independent Investigatorship Award
  • 2004: Outstanding Research for Young Scientist, Human Genome Organization (HUGO)
  • 2004: A*STAR AGS Scholarship
  • 2002: A*STAR-BII M.Sc. Scholarship

GRANTS

  • 2024: PREPARE (MOH) – Discovery of anti-influenza A therapeutics with a strategy for simultaneous heterosubtypic targeting that hedge against drug resistance (PREPARE-OC-VT-2024-002)
  • 2024: Selective targeting isoform-specific FynT tyrosine kinase. STDR PILOT
  • 2024: Expanding multiplexing capabilities for digital PCR method for absolute quantification of gene panels in clinical diagnostics. A*STAR Decentralised GAP (I24D1AG003)
  • 2024: Anti-inflammatory skin moisturizer for management of atopic eczema. NHG CMTi – NHIC Joint Medtech Grant Call (CMTi-NHIC5-23-01-01)
  • 2021: IAF-PP (A*STAR BMRC) – A Multitiered Platform Technology for Targeted Delivery and Release of RNA Therapeutics (H20H7a0034)
  • 2021: Anti-inflammatory moisturizer cream containing oligonucleotide for management of atopic eczema. 2nd NHG CMTi – NHIC Joint Medtech Grant Call
  • 2020: IAF-PP (A*STAR BMRC) – A Comprehensive Precision Medicine Platform for Rare Genetic Disorders
  • 2020: Therapeutic targeting of mutant p53 as an approach to improve cancer therapy. NHIC I2D Grant Call 18
  • 2020: Engineering Smart Pandan-ribozymes activated by RNAs (SPARs) for context-specific release of functional RNAs. ESCO-Platinum Grant
  • 2020: Modulation of p53 splicing as an approach to improve cancer therapy. NMRC OF-IRG
  • 2019: Targeting GLDC with shAONs as a therapeutic strategy for liver cancer and gliomas. A*ccelerate GAP (Gene & Cell Therapy)
  • 2019: Targeting PRDM15 with shAONs as a therapeutic strategy for liver cancer and gliomas. A*ccelerate GAP (Gene & Cell Therapy)
  • 2018: Steric Hindrance Antisense Oligonucleotide (shAON) Library for Splicing Modulation of Human Transcriptome. ETPL GAP I & II
  • 2018: Modulation of alloreactivity, efficacy and function of TCR-redirected T cells for clinical application. IAF-ICP
  • 2017: Combinatorial strategies to enhance immunotherapy of viral associated tumors. 17th NRF CRP
  • 2017: Identification and Validation of PRDM15, a novel epigenetic target in oncology. NMRC OF-IRG (transferred)
  • 2013: Development of technologies based on antisense oligonucleotides (AONs)-mediated splicing modulation, and designing of optimal therapeutic application for untreatable acute leukemias and imatinib-resistant chronic myeloid leukemia. A*STAR Joint Council Office Project Grant
  • 2012: Design of efficient antisense oligonucleotides drugs for the therapy of human diseases. IHPC Independent Investigatorship


RESEARCH
Transcriptome Modulation through Rational RNA Engineering
Dave’s research at IMCB centers on developing platform technologies to modulate the human transcriptome with high precision and throughput. His group uses chemically modified steric hindrance antisense oligonucleotides (shAONs) to target specific RNA sequences and alter splicing, stability, or structure. These shAONs can block RNA-binding proteins or reshape local RNA conformations to influence diverse RNA processing events such as exon inclusion or skipping, alternative splice site usage, and transcript transport. By combining experimental methods with computational and biophysical modelling, the team designs rational intervention strategies that can be scaled across the entire transcriptome.

RNA Therapeutics from Target Discovery to Precision Drug Design
In parallel, the lab focuses on RNA therapeutics, bridging target discovery to the development of drug candidates using the same shAON-based mechanisms. This approach enables a streamlined pipeline where therapeutic leads can be rapidly derived from screening hits. Ongoing projects include developing shAONs that trigger nonsense-mediated decay for transcript silencing, and designing “bi-therapeutics” that simultaneously suppress disease-causing isoforms and restore normal ones by correcting pathological splicing. Their custom-built screening platform allows for phenotype-driven identification of functional splice variants, enhancing both target confidence and therapeutic precision.


PUBLICATIONS PATENTS
  • Dna construct and nucleic acid compound tools (PCT/SG2024/050628)
    The present invention provides a DNA construct comprising: (a) a starter exon encoding a start codon; (b) a first frame-switch exon located downstream of the starter exon, the first frame-switch exon comprising a first acceptor splice site, wherein inclusion or exclusion of the first frame-switch exon during alternative splicing determines the downstream reading frame of the mature mRNA transcript; and (c) a first specific exon located downstream of the first frame-switch exon, the first specific exon comprising a second acceptor splice site, a first reporter gene and a second reporter gene, wherein the first reporter gene is upstream or downstream of the second reporter gene and wherein the first reporter gene is in a different reading frame from the second reporter gene, wherein the exclusion of the first frame-switch exon causes the first reporter gene to be in-frame with the start codon and wherein the inclusion of the first frame-switch exon causes the second reporter gene to be in-frame with the start codon.

  • Modified U1 snRNAs (PCT/SG2024/050477)
    The present invention relates to modified U1 snRNAs configured to rescue exon skipping in a mutated ABCA4 gene. In one aspect of the present invention, there is provided a modified U1 small nuclear RNA (snRNA) configured to retain exon 40 in a mature mRNA transcript of a mutated ABCA4 gene, the mutated ABCA4 gene comprising a mutation that induces skipping of exon 40, wherein the mutation is located between 3 base pairs upstream and 8 base pairs downstream of a donor splice site of exon 40, wherein the modification comprises replacing a portion of a single-stranded nucleotide sequence of a 5' region of a wild-type U1 snRNA with a single-stranded binding nucleotide sequence capable of hybridizing to a target sequence present on a pre-mRNA transcript of the mutated ABCA4 gene, and wherein the target sequence is located in a region between 13 base pairs upstream and 15 base pairs downstream of the donor splice site of exon 40. In another aspect, there is provided a nucleic acid construct comprising a polynucleotide sequence encoding the modified U1 snRNA as described herein.

  • Splice-switching oligonucleotides targeting IL-4Ra (PCT/SG2023/050576)
    The present invention relates generally to the field of RNA splicing. In particular, the invention relates to splice-switching oligonucleotides (SSOs) configured to alter the splicing of a IL-4Rα pre-mRNA. The invention also relates to a method of exon-skipping wherein the binding of the SSO to a IL-4Rα pre-mRNA induces the exclusion of an exon during splicing of the IL-4Rα pre-mRNA to a IL-4Rα mature mRNA. The invention also relates to the use of SSOs as therapeutic candidates for treating Th2-mediated inflammatory diseases.

  • Oligonucleotides (PCT/SG2023/050470)
    The present invention relates generally to the field of RNA splicing. In particular, the invention relates to splice-switching oligonucleotides (SSOs) that bind to mRNAs encoding synthetic lethality targets of Myc. In one aspect, the invention relates to a SSO that binds to a pre-mRNA or mature mRNA of a BRD4 gene, wherein binding of the SSO inhibits functional expression of the BRD4 gene, in another aspect, the invention relates to an SSO that binds to a pre-mRNA or mature mRNA of a CHEK1 gene, wherein binding of the SSO inhibits functional expression of the CHEK1 gene. The invention also relates to the use of SSOs as therapeutic candidates for treating Myc-driven cancers.
  • Oligonucleotides (PCT/SG2023/050458)
    The present invention relates to splice-switching oligonucleotides (SSOs) capable of altering the slicing of a pre-mRNA encoding a variant of the SLC25A13 gene, as well as the use of the same SSOs for treating citrin deficiency. In an embodiment, a SSO that binds to a site within a target region present on a pre-mRNA transcript of the SLC25A13 gene, wherein the binding of the SSO induces the exclusion of SLC25A13-PE5 from a mature mRNA transcript of the SLC25A13 gene. In another embodiment, the target region having at least 95% sequence identity to SEQ ID NO: 28.
  • Antisense oligonucleotides for modulating the function of a T cell (WO/2019/004939)
    The present invention relates to antisense oligonucleotides for modulating the function of a T cell, including antisense oligonucleotides that hybridise to IFN-γ, granzyme, perforin 1, PD-1, PRDM1, PD-L1, CD40LG, NDFIP1, PDCD1 LG2, REL, BTLA, CD80, CD160, CD244, LAG3, TIGIT, ADORA2A & TIM-3 RNAs. In particular, the present invention relates to antisense oligonucleotides capable of inducing exon skipping of RNA. Also claimed is a method for further modifying the specificity of said T-cell by providing for a T cell receptor gene.
  • Method for screening splicing variants or events (WO/2019/032054)
    The present invention relates to a high-throughput method of screening splicing variants of target genes as drug targets or for characterisation of their biological functions. The disclosure provides a method for the screening of splicing variants, comprising: (a) providing a first antisense oligonucleotide capable of inducing a first splice event on the target gene to express a first splicing variant, and a second antisense oligonucleotide capable of inducing a second splice event on the target gene to express a second splicing variant; (b) hybridising the first and second antisense oligonucleotides to a pre-mRNA of the target gene; and (c) characterising the effect of the splice event. In one embodiment, the first antisense oligonucleotide switches the splice event that expresses the second splicing variant towards one that expresses the first splicing variant, while the second antisense oligonucleotide switches the splice event that expresses the first splicing variant towards one that expresses the second splicing variant.

  • Method of treating cancer by antisense oligonucleotides targeting PRDM15 (WO/2018/044239)
    The present invention relates to antisense oligonucleotides for modulating the activity of PRDM15 and use thereof in the treatment of cancer. In particular, said antisense oligonucleotides are capable of inducing the skipping of an exon of a PRDM15 mRNA. The present invention also relates to a method for determining prognosis in a patient with cancer, or selecting a therapeutic strategy for a patient with cancer, by assessing the level of PRDM15 nucleic acid, protein or activity in a sample.
  • Antisense oligonucleotides (WO/2018/080393)
    The present invention relates to antisense oligonucleotides for modulating the activity of glycine decarboxylase (GLDC). In particular, the present invention relates to antisense oligonucleotides capable of inducing exon skipping of RNA. Also claimed are pharmaceutical compositions, kits and methods of treating cancer and inducing exon-skipping using said antisense oligonucleotides. In addition, a method for aiding the categorising or determining prognosis of a cancer or in selecting a therapeutic strategy for a patient with cancer, based on assessing the level of GLDC nucleic acid, protein or activity in a sample derived from the patient is provided.