How they’ve leveraged their biobank into discoveries.
Novel gene editing technologies are coming – human examples are here as well.
CAG @ CHOP, founded in June 2006. Recruit enough children that even rare conditions become common. About 100,000 kids have been recruited, 70,000 can be reconnected with. Almost 300,000 samples through collaborations in addition.
An early disease that was worked on, Neuroblastoma – usually found in advanced stages. Hard to treat.
Found some markers. 1% hereditary, 99% sporadic.
12% of sporadic cases had ALK mutations. Existing drug for that, so was able to go straight to trial, which was successful and rapid.
Another project: Neurocognitive phenotyping. [Huge data collection effort, covering a very broad set of data gathering methods] ADHD was a component of it. Identified CNV in cohort, which clustered on Glutamate receptors in the brain (Elia, Glessner et al, 2011) Replicated in 5 different cohorts. CNVRs overrepresented in cohort.
Have seen similar things in other neurocognitive diseases.
At the time, there was no drug for mGlutR Pathway. There was, however, a drug that was indicated for another disease, but didn’t make it to the market. Found up to 20% of patients have glutamate copy number variants. They undertook new studies to demonstrate that the drug was useful for ADHD that have these mutations. End up approved by FDA, down to 12 years of age. IRB in November 2014, completed by May 2015. Efficacy was extremely robust in this preliminary setting. 80%of patients had improvement following highest dose.
Expanded to included new mutations that influence mGLuR signalling, then expanded further to genes that influence that.
Tier one response was much stronger, those with mutations in the expansion groups did not have as high responses.
Some overlap with children who had co-morbid autism (including 22q deletion). Major improvement in social behaviour and language.
Started a separate trial for 22q11.2 deletion syndrome based on effects seen in earlier results.
Repurposing compounds that already have safety data makes for rapid drug trials.