Chris Hopkins, PhD, MBA and CSO patient variant drug p.R292H - - PowerPoint PPT Presentation

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Apr 02, 2023 267 likes •500 views

Chris Hopkins, PhD, MBA and CSO patient variant drug p.R292H pathogenicity Is this variant in my patient pathogenic or benign? "The Doctor" by Sir Luke Fildes (1891) Drop in genome price drives increase in patient variant

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Chris Hopkins, PhD, MBA and CSO

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variant pathogenicity drug

p.R292H

patient

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Is this variant in my patient pathogenic or benign?

"The Doctor" by Sir Luke Fildes (1891)

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Drop in genome price drives increase in patient variant observations

Since 2016, clinical testing up more than 6x

ClinVar variant observations submissions Moore's law Cost per genome clinical testing literature only research curation

ther

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Observed variants are small fraction of theoretical

80,000,000 possible 0.27% path matter dark

https://clinvarminer.genetics.utah.edu

0.15% benign

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Observed variants are in 3 major classes

Benign Pathogenic

VUS

36% 19% 42%

n.d.

https://clinvarminer.genetics.utah.edu

Variants of Uncertain Significance

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Observed variants in established genes still have VUS problem

Well studied genes

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Hot spots and cold spots in STXBP1

highMAF: TOPMED, GnomAD, ExAC, GO-ESP, 1000G

STXBP1 gene has regions where pathogenicity is likely

(benign)

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Installing genetic variation in small animals creates a diagnostic tool for VUS functional studies

Understand disease mechanism
Personalized therapeutics

Nematode (C. elegans) Zebrafish (D. rerio)

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Discovery platform occurs in three phases

Humanize: Gene-Swap Technique

Phase I

Variant Install: measure functional defects

Phase II

Best-Fit: screen existing AEDs

Phase III

Personalized proxy of patient

Clinical Avatar

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Humanize: Geneswap of STXBP1 rescues function

human nematode Gene (STXBP1) Gene (unc-18)

4 KO Electrophysiology (Hz)

human gene 2 WT

* nd

Phase I

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Clinical Avatars are tested for pathogenicity

p.Arg406His Benign Pathogenic

? R406H KO ? R406H KO

Variant install:

Humanized Phase II

human gene human gene

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Functional testing demonstrated on two systems

Pathogenic R406H variant showing minimal deviation from normal
R122x deviant in electrophysiology, Y75C deviant in movement

h u m a n g e n e

Y 7 5 C R 4 6 H R 1 2 2 x

h u m a n g e n e

Y 7 5 C R 4 6 H R 1 2 2 x

Electrophysiology Movement

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R406H has phenotype by eye

hSTXBP1-wt hSTXBP1-R406H hSTXBP1- Knock Out

Need multiple parameter testing

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PCA plot detects subtle differences

Variants are in distinct and non-overlapping clusters
1
2
3

1 2 3 4 4

2 6 8 10 PC2 morphology P C 3 PC1 movement R122x Y75C human gene R406H

MBF

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PCA plot of ephys also separates variants

Each variant in different clusters

R122x Y75C human gene R406H P C 2 PC1 PC3 Frequency i n t e n s i t y

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Drug screening on STXBP1 Clinical Avatars

Formats up to 1536 well
Multiparameter measurements

Benign Pathogenic EC50

Restore wild type behavior

Best-Fit:

Phase III

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Clinical Avatars validate AI generated hits

Chemical rescue Clinical Avatar

Clinical Variants modeled in STXBP1 hits activity

Hits giving rescue move forward in drug development pipeline

p.R406H

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Targeting 100 variants for Clinical Avatar creation

55 identified (24 ready), 45 more to go

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Precisome targets:

Genes correlated with seizures and neurological other targets

Ataxia Epilepsy Neurodegen

STXBP1 SCN1A KCNQ2 CDKL5 MTHFR LMNA POLG SLC2A1 ATP1A3 CACNA1A MAPT TARDBP GRN C9orf72 AAP PSEN1 NALCN SNC2A

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Matthew Bainbridge Ingo Helbig Katherine Helbig Heidi Rehm Phil Pearl Anne Johnson Charlene Son Rigby Tom Caulfield Dave Freedman William Tatum Miguel Weil Lior Dor Fowzan Alkuraya Michael Kruer STXBP1 Foundation

Acknowledgments

CHOP Harvard Rady Phoenix King Faisal Mayo Tel Aviv

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