Project 8p Research Newsletter - April 2023
💬 Research Question of the Month
What happens when preliminary data from two independent model systems line up? Is it case closed, or just the beginning of a careful iterative process to determine which results are real and which results are not, i.e, false positives? In this case, one model is three-dimensional cortical brain organoids grown in the lab for nine months, and the other model is two-dimensional glutamatergic neurons grown in the lab for three weeks. As much as we want to believe initial positive results, they have to be rigorously repeated and pressure-tested. For any iPSC-derived model, it’s imperative to use multiple independent clones or models from additional 8p hero- derived samples.
Let us know what you think in the Comments section below!
🔬Research Highlight
At last month’s Research Roundtable, Dr. Joe Bellucci - Director of High-Throughput Biology at Rarebase - shared their FunctionTM platform and its application to 8p. Their platform uses a combination of cell models, high-throughput drug screens, and computational analyses to identify potential disease-modifying therapies for rare diseases. To identify potential therapeutic targets in 8p, they compared global gene expression in glutamatergic neurons derived from an invdupdel 8p hero to those derived from control iPSCs. The analysis showed many differentially expressed genes, including many genes on chromosome 8p. The next step will be to determine which of these genes are the most promising therapeutic targets.
Featured image (above): Differential expression of genes in 7- and 21-day-old invdupdel 8p cortical glutamatergic neurons compared to control neurons. Genes indicated in pink are on the p arm of chromosome 8 and those indicated in green are the top 10 most differentially expressed genes.
Watch the March Research Roundtable on Project 8p’s YouTube channel to learn more
💡Did you know?
Thanks to Dr. Stefan Pinter for sharing these observations during the March Research Roundtable!
It is common for iPSCs to undergo unplanned changes in lab culture settings. Dr. Pinter highlighted two such changes during our Research Roundtable: 1) Iso20q is a common chromosomal rearrangement that occurs during prolonged culture because it provides a selective growth advantage in cell culture (McIntire et al. 2016, Nguyen et al. 2013). 2) Loss of XIST expression in female iPSCs can lead to reactivation of the inactive X chromosome (Bansal et al. 2021). Inactive X erosion can have effects on translation (Brenes et al. 2021), negatively impact the ability of the cells to differentiate, and can lead to confounding cellular phenotypes. This observation does not necessarily preclude the use of female iPSCs in research, but is something to be aware of as experiments are designed and carried out.
🧠 Highlights from the Gordon Research Conference on Functional Genomics of Human Brain Development and Disease
Above: Project 8p’s CEO and President, Bina Shah, and her co-founders of the Commission on Novel Technologies for Neurodevelopmental CNVs, Vanessa Vogel Farley and Yssa DeWoody, presented the commission’s work at the conference.
We’d like to spotlight the major theme from the conference last week: tool building. Whether it was exploring novel bioengineering approaches to grow more faithful, more reproducible and more complex brain organoid models, and or developing CRISPR-based tools to interrogate and program gene function at scale, every speaker and poster presenter was pushing the frontier of technology.
The co-heads of the AbuGoot Lab at MIT gave a whirlwind presentation on all of the burgeoning gene editing technologies. Nothing is ready for prime-time as far as chromosome therapies are concerned, but this is exactly the moment for a group like Project 8p to make seed investments in this space.
The Kampmann Lab at UCSF is a CRISPR screening and single-cell RNAseq powerhouse. Project 8p is very interested in applying these tools in order to assess the contributions of 8p genes to disease phenotypes in the lab.
When this GRC meets again in two years, we hope there will be many more patient voices in the audience: nothing about us, without us
📄 Recent Articles and Publications
Let us know if you’ve read or published a paper or article recently that you think the 8p community should know about!
Are we prepared to deliver gene-targeted therapies for rare diseases? Yu, T. W. et al. (2023). AJMG, 193C: 7– 12. https://doi.org/10.1002/ajmg.c.32029 (Open Access)
In this commentary, Dr. Timothy Yu and colleagues discuss the challenges of moving from the current model of newborn screening for diseases with existing therapeutics, to a model of widely accessible whole-genome screening and precision gene-targeted therapies.
Data sharing to advance gene-targeted therapies in rare diseases. Lekstrom-Himes, J., et al. (2023). AJMG, 193C: 87– 98. https://doi.org/10.1002/ajmg.c.32028 (Open Access)
In 2021, the NIH hosted a 3-day roundtable on “Gene Targeted Therapies: Early Diagnosis and Equitable Delivery,” aimed at improving access to safe and effective gene-targeted therapies, such as ASOs and CRISPR-mediated gene editing. This article discusses the insights from that meeting around data sharing, and also presents several case studies highlighting the successes and challenges of global patient registries.
Telomere-to-telomere assembly of diploid chromosomes with Verkko. Rautiainen, M., et al. Nat Biotechnol (2023). https://doi.org/10.1038/s41587-023-01662-6
Here, Rautiainen et al. describe a new long-read assembly pipeline that enables phased assembly of diploid genomes. At an upcoming Research Roundtable, Dr. Glennis Logsdon will share the results of implementing Verkko to assemble the complete sequence of chromosome 8 from a hero with an 8p inverted duplication and deletion.
Network and Microcircuitry Development in Human Brain Organoids. Puppo, F. and Muotri, A. https://doi.org/10.1016/j.biopsych.2022.07.006
In this Commentary, Dr. Puppo and Dr. Muotri discuss the ways in which cortical organoids do and do not recapitulate the networks and structures observed in developing and mature human brains, as well as some of the methods and challenges for analyzing their function.
💜 Family Corner
We achieved our first My Hero Initiative goal of 25 heroes in the Chromosome 8p Registry and Rare-X 8p Data Collection Program. To celebrate, we will be giving away 4 Amazon gift cards. Be sure to check your email.
Researchers have asked for skin donations (US families currently) to expand to more 8p heroes and a biological parent. This will help facilitate a few more studies we need to validate preliminary results.
Chromosome 8p Registry Users, it is time to complete your first 2023 Participation Sign On. If you have not already done so, please log into the registry and ensure surveys are complete and updated, if need be. Continuous engagement from our community is vital for ongoing data collection, aggregation and analysis. Thank you for adding your piece to the Chromosome 8p Puzzle.
Need Assistance? Email kaiti@project8p.org
📆 Upcoming Events
May 1st - 3rd - Bina Shah, Founder will be at the RARE Drug Development Symposium by Global Genes, in partnership with the Orphan Disease Center (ODC) at the University of Pennsylvania School of Medicine
COMING SOON - 8p Scientific Meeting in October!