Project 8p Research Newsletter - May 2023
💬 Research Question of the Month
How should the 8p community be preparing for drug repurposing and biomarker discovery? Those are two 8p-hero-powered initiatives that can deliver clinically actionable results quickly relative to the pace of academic research. While disease modeling results start to flow in from the projects that Project 8p funded last year, the 8p community can itself advance research and take matters in their own hands by self-organizing around drug repurposing and biomarker discovery.
Let us know what you think in the Comments section below!
🔬Research Highlight
This month we tried something different at the Research Roundtable. Instead of having one or two researchers present their work, we posed several research questions to the group and then opened the floor for discussion. The experiment clearly worked, as there was a great exchange of ideas and knowledge, from both researchers and families.
The first question discussed was around the re-analysis of transcriptomic data. Transcriptomic data provides a snapshot of information about the genes being expressed at a given point in time in a cell or group of cells. To date, we have collected RNAseq data on 8p fibroblasts, glutamatergic neurons derived from iPSCs, and cortical (brain) organoids. In addition to using these data to understand the expression of genes on chromosome 8p, we can also interrogate the effects of 8p CNVs/SVs on gene expression more globally in order to identify cellular pathways or specific gene drivers that might contribute to disease pathology, or that could even be targeted pharmacologically. One of our first approaches will be to use the fibroblast RNAseq data to inform ongoing efforts to identify cellular phenotypes that could be used for drug repurposing screens. If any of these data could be useful to your 8p research project, please get in touch.
The second question the group discussed was how we can start to assess the risk of accelerated aging in 8p heroes. The limited clinical data that we have on adult 8p heroes suggests that some may experience features of accelerated aging, similar to individuals with Down’s Syndrome. Many of our experiments are done using iPSCs; however, the process of creating iPSCs resets the age of the cells such that epigenetic markers of aging are lost (Horvath, S. 2013). One alternative is to use a process of direct differentiation to go from a collected biospecimen to the cell type of interest, such as neurons, skipping the iPSC stage altogether, but this can be a long and technically challenging process. The group agreed that the first step should be to determine whether cells from 8p heroes have alterations in their epigenetic clocks by comparing DNA methylation in samples collected from 8p heroes of different ages. These experiments are relatively straightforward, and can be done from a number of different types of biospecimens. Based on the results of such experiments, we could then decide whether direct differentiation is worth pursuing.
You can watch the whole discussion on Project 8p’s YouTube channel:
💫 Coming Soon: The Project 8p Insights Portal
Project 8p’s various sponsored research projects are beginning to produce a lot of exciting data. To make the most of this data, and in keeping with our Open Science policy, we aim to make the data as widely available to the community as possible. To achieve this, we are creating The Project 8p Insights Portal. The portal will include experimental data and patient survey data collected through our registries, as well information about available biospecimens. From this online portal researchers and clinicians will be able to perform cohort analyses, visualize data, and request samples and raw data. The portal will also serve as a way for patient families to more easily see and contribute their data.
We plan to roll out the first iteration of the portal later this year.
📄 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!
KaryoCreate: A CRISPR-based technology to study chromosome-specific aneuploidy by targeting human centromeres. Bosco, N et al. Cell. Apr 2023 https://doi.org/10.1016/j.cell.2023.03.029.
KaryoCreate is a molecular technique that can be used to create arm-level and chromosome-level gains and losses. The technique could be employed to study the effects of loss or duplication of 8p in isolation. Thanks to Dr. Matt Lalli for sharing this paper with us!
A Critical Review of the Impact of Candidate Copy Number Variants on Autism Spectrum Disorders. Abedini, SS et al. arXiv:2302.03211v2 [q-bio.GN]. Mar 2023. https://doi.org/10.48550/arXiv.2302.03211 Open Access. *This a pre-print and has not yet been peer reviewed.
Abedini et al. review the protein-coding genes and long noncoding RNAs found within 47 autism spectrum disorder (ASD)-associated CNV regions. To identify ASD candidate genes, they looked at their expression in the brain and during iPSC to neuron differentiation, as well as whether mutant mice showed any nervous system phenotypes. On chromosome 8p they looked at deletions on 8p23.1 and identified TNKS, PINX1, MSRA, XKR6, FAM167A, NEIL2, RP1L1, GATA4, and lncRNA RP11-1E4.1 as possible contributors to ASD.
Targeting RNA with small molecules: lessons learned from Xist RNA. Nickbarg, EB. et al. RNA. Apr 2023 https://pubmed.ncbi.nlm.nih.gov/36725318/ Open Access.
Most drugs on the market target disease causing proteins, however long noncoding RNAs are becoming increasingly appreciated as drivers of disease. RNAs are more difficult to target though due to the numerous confirmations they can adopt. This perspective discusses recent success with a structure agnostic way to screen for RNA-binding small molecules using affinity-selection mass spectrometry.
New 8p Case Reports:
Expanding the Phenotype of 8p23.1 Deletion Syndrome: Eight New Cases Resembling the Clinical Spectrum of 22q11.2 Microdeletion. Montenegro, MM. et al. J Pediatr. Jan 2023. https://doi.org/10.1016/j.jpeds.2022.08.051
Insight into the 8p23.1 duplication syndrome: Case report of a young woman with infertility. El Karaaoui, AK. et al. Heliyon. Apr 2023. https://doi.org/10.1016/j.heliyon.2023.e15515 Open Access.
8p Microdeletion Syndrome Presenting as Congenital Scoliosis and Facial Dysmorphism with Novel Anomalies. Ansari, FF. et al. SAS J Med. Mar 2023. https://saspublishers.com/article/14392/ Open Access.
💜 Family Corner
My Hero Initiative is seeking adult 8p heroes!
Demographic diversity is a critical component of natural history studies; this month, we want to highlight the importance of age cohorts. We need representation from all age groups to understand how the disease progresses over time. Participation from our adult 8p heroes is low; our research team is recruiting 8p heroes aged 16+. To learn more about participating and enroll your hero, please email kaiti@project8p.org
All My Hero Initiative Participants:
We are excited to announce that our Partners at Rare-X are utilizing mobile phlebotomy for biorepository blood sample collection. At no cost to you, a phlebotomist can come to your home and collect a sample. Participation in the Rare-X 8p Data Collection Program is required. Email kaiti@project8p.org to get started.
📆 Upcoming Events
8p Research Roundtable, Dr. Stefan Pinter, May 22nd 1:30 PM EST. Email whitney@perlara.com or kaiti@project8p.org if you would like to attend.
Drug Repurposing Town Hall, May 26th 11:30 AM EST. Email kaiti@project8p.org if you would like to attend.
8p Scientific Meeting coming in October!
🌐 Find us on the web
FACEBOOK | INSTAGRAM | TWITTER | LINKEDIN | YOUTUBE
Founded in November 2018 as a 501(c)(3) nonprofit, Project 8p Foundation works to empower a unified community for chromosome 8p heroes for a meaningful life today while accelerating treatments for tomorrow.