Timothy Yu of @bostonchildrens.bsky.social highlighted how antisense oligonucleotide therapies are transforming possibilities for rare pediatric neurological diseases, offering new hope for families. #AGBTPH25
2
0
1
0
Hashtag
#AGBTPH25
Advertisement · 728 × 90
#AGBTPH25 JY: Can do all by all testing of compounds x cancer models. 50 cancer models, 1200 drug treatments, 60K experiments, 100M cells
0
0
0
0
#AGBTPH25 Johnny Yu from Tahoe Therapeutics to talk about virtual cell models. Single cell work has advanced dramatically in 10 yrs
0
0
0
0
#AGBTPH25 JK: Could apply functional data to reclassify 682 VUS. Look at All of Us data, rare LOF missense have higher risk of cancer. AlphaMissense prediction calls too many variants pathogenic
0
0
0
0
#AGBTPH25 JK: Lynch syndrome is first inherited cancer risk syndrome, LOF in DNA mismatch repair genes. Most are missense with most being VUS. Apply 6-TG to cells to select MMR- proteins. Mapped 73,568 missense variants. Most have no effect but there are hot spots for impact
0
0
0
0
#AGBTPH25 Jacob Kitzman from UMich will talk about variants in hereditary cancer syndromes
0
0
0
0
#AGBTPH25 TY: N=1 collaborative working on sharing knowledge and guidelines for use, need innovative regulatory models
0
0
0
0
#AGBTPH25 TY: Another dozen genes being treated, more than 30 patients so far. ASOs great version 1 but gene editing could have broader applications
0
0
0
0
#AGBTPH25 TY: de novo KCNT1 R474H mutation leads to increased channel firing. Used ASO to shut down mutant protein. Daily seizures dropped from 10-15 to 0-2 and stayed down for 50 days but patients developed hydrocephalus. Now being tracked for other ASOs, try to keep dose lower.
0
0
0
0
#AGBTPH25 TY: Proposal for N=1 medicine to help patients with no other options. Led to FDA guidance for individualized medicine. New trials in ATM kinase, KCNT1 and FLVCR1. ATM trial is longest running N=1. Have seen no clinical progression on primary outcomes.
0
0
0
0
At #AGBTPH25, @hcmefford.bsky.social of @stjuderesearch.bsky.social shared how gene replacement and antisense therapies are advancing treatments for rare pediatric epilepsies and neurological diseases — bringing new hope to patients and families.
#PrecisionHealth #Genomics #RareDisease #Epilepsy
6
2
1
0
#AGBTPH25 TY: Milasen is ASO that introduced N=1 medicine. SIgnificantly lowered seizure frequency and improved quality of life but did not save life. Post-mortem studies showed it was working.
0
0
0
0
#AGBTPH25 TY: Going straight from genetics to therapeutics will increase efficiency. Antisense oligonucleotides (ASOs) are easy to manufacture, easy to predict effects, multiple uses
0
0
0
0
#AGBTPH25 TY: Mind the gap. Genome sequencing has shortened diagnostic odyssey but not the path to therapy. Many rare diseases are too rare to be commercially investable. Not obvious they weren't being addressed because causes unknown. Now we know what we're not doing.
0
0
0
0
#AGBTPH25 Tim Yu from BCH/Harvard Med talking about interventional genetics.
0
0
0
0
#AGBTPH25 HM: ongoing trials of targeted therapies including SCN1A with ASO targeting poison exon and a cell selective gene therapy. For SCN2A, ASO knockdown. How to scale? 13 genes with ASO in preclinical development, 5 in clinic or trial
0
0
0
0
At #AGBTPH25 @sbmontgom.bsky.social of Stanford shared how integrating genomic and molecular data can uncover hidden disease mechanisms and improve diagnostics. A powerful step forward for rare disease research and precision medicine.
#Genomics #PrecisionHealth
0
0
1
0
#AGBTPH25 HM: UBA5 Dad was Hypo/+, mom was LOF/+. Child was Hypo/LOF. Hypo/Hypo can be healthy so try to boost expression of Hypo allele. Tried SINEUPs using lncRNA and CRISPR dCAS9 with activator domain to boost protein expression
0
0
0
0
#AGBTPH25 HM: identify the target, model the disease, engage patients. Can try gene replacement, ASOs, gene editing, gene regulation
0
0
0
0
#AGBTPH25 HM: developmental and epileptic encephalopathies - most drugs don't work; early onset, intractable seizures; hundreds of genes identified, 50% diagnostic rate, de novo variants are important, overlap with ID, autism
0
0
0
0
#AGBTPH25 Heather Mefford from St Jude Childrens Hosp to discuss precision diagnosis to targeted therapies in epilepsies.
0
0
0
0
#AGBTPH25 SM: Used CRISPR to change isoform abundance (DESeq2). Depletion strongly enriches isoforms expressed in nerve, muscle, adipose, and skin. Depletes blood, spleen, small intestine, lung. Can find intron retentions not normally visible in blood
0
0
0
0
#AGBTPH25 SM: Looked at outliers of outliers of splicing.
See people with hundreds of intron retentions. Even more dramatic if look at only products of minor splicesome. 5 had mutations in RNU4ATAG, one RNU12
0
0
0
0
#AGBTPH25 SM: If look at extreme outliers, can narrow down to a handful of individuals. Looked at teenage girl with apparent overgrowth syndrome, not Prader-Willi. Saw region on chr11 with reduced methylation near 2.7Mb. If look at all genomes, z score goes from -7.5 to -6.8
0
0
0
0
#AGBTPH25 SM: outlier molecular phenotypes can inform gene function. Looking at methylation outliers. Find deviant regions relative to the whole population. How unusual is a particular pattern?
0
0
0
0
#AGBTPH25 SM: Gregor - Genomics Research to Elucidate the Genetics fo Rare Diseases. U11 release >1000 RNAseq, lots more DNA seq
0
0
0
0
#AGBTPH25 SM: multi omics being used increasingly but usually applied to only a few cases and controls
0
0
0
0
#AGBTPH25 SM: Whole genome sequencing at scale increases likelihood of finding variants but increases interpretation burden. What is the strategy most likely to be effective for a patient?
0
0
0
0
#AGBTPH25 Stephen Montgomery from Stanford to talk about multi-omics strategies for diagnosis of rare diseases.
0
0
0
0
#AGBTPH25 JS: 3 factors and dosage give each disease a distinct signature
0
0
0
0