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  • January 17, 2025
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Date: January 23, 2025
Time: 11-12pm EST

Title: Antisense oligonucleotides targeting linked-SNPs provide allele-specific knockdown of a dominant-negative SPTAN1 pathogenic variant

Description:

Our first webinar of the year features trainees Christiana Wang, Elaine Kang, and Sinan Faiad, all of whom won poster awards at the 2024 Annual Meeting.

Presentation Description:

Developmental and epileptic encephalopathy 5 (DEE5) is a rare neurodevelopmental disorder caused by monoallelic pathogenic variants in SPTAN1, which encodes non-erythrocytic αII-spectrin. We enrolled five children with DEE5 and the duplication variant from four families. The affected children presented with hypotonia, cerebellar hypoplasia, microcephaly, cortical visual impairment, and infantile tonic seizures. We performed genome sequencing to identify candidate heterozygous exonic and intronic linked single nucleotide polymorphisms (SNP) and designed antisense oligonucleotides (ASOs) that knocked down targeted allele. Priorities were given to SNPs that exhibited promising sequencing features supporting ASO potential or higher population frequencies, allowing a broader application for future translation. Our approach establishes a framework for employing patient-derived cells to screen and validate RNaseH-dependent ASOs for managing dominant-negative neurological disorders and developing personalized treatments.

Speaker:

Christiana Wang, PhD Candidate
Baylor College of Medicine

Title: Strategic Modification of DNA Nanocubes for Improved Biological Activity

Presentation Description:

DNA nanocubes modified with site-specific disulfide monomers are used to covalently crosslink the structure. Crosslinked nanocubes exhibit enhanced stability in serum due to improved resistance against exonucleases. This enhanced stability allows for the structural maintenance of the nanocube which facilitates cellular uptake via scavenger receptors. Non-crosslinked nanocubes are degraded and do not engage the same uptake pathway into cells.

Speaker:

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Sinan Faiad, PhD candidate
McGill University

Title: Lipid Nanoparticle Formulations for the Delivery of CpG-STAT3 siRNA to Myeloid Immune cell for Cancer Immunotherapy

Presentation Description:

We previously demonstrated that blocking tolerogenic STAT3 signaling in the tumor microenvironment can unleash Toll-like receptor 9 (TLR9)-mediated antitumor immune responses. Our proof-of-concept approach, an unformulated CpG-STAT3siRNA oligonucleotide, proved effective in preclinical studies in mice against human and mouse tumor models, such as leukemia, B-cell lymphoma, melanoma, glioma, bladder, and colon cancers. To optimize this strategy, we screened and optimized myeloid immune cell targeted lipid nanoparticle formulation to enhance the therapeutic effect of CpG-STAT3siRNA in B cell lymphoma models. Our results suggest that optimized LNP2.1 formulation can improve myeloid cell activation and recruitment into t-dLN, and thus lead to improved T cell-mediated tumor control.

Speaker:

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Elaine Kang, PhD
City of Hope, Beckman Research Institute