We previously announced our collaboration agreement with StrataStem involving a large-scale library of human iPSCs derived from patients with Alzheimer’s Disease. In this short article, we discuss the vision for an Alzheimer’s Disease “clinical trial in a dish” model and new insights from a recent study on the StrataStem Manchester Cohort.
Human iPSC models could transform AD drug discovery
Alzheimer’s Disease (AD) is the most common form of dementia, affecting over 40 million people worldwide with an estimated annual societal cost of over $1 trillion [1]. With an aging world-wide population, rates of AD are predicted to triple by 2050 resulting in a global cost of over $9 trillion per year [2].
There is a high rate of failure in AD drug development, with 99.6% of trials showing no clinical effect [3]. Despite new AD therapeutics becoming available, there remains a lack of understanding of the molecular and cellular mechanisms associated with early and prodromal stages of the disease. This is especially true for sporadic Alzheimer’s Disease – which makes up 95% of AD cases – where there is no clear cause or family history. To decrease drug development failure rates, industry will need to address the significant clinical and molecular heterogeneity that has hindered progress thus far.
We’re excited about the concept of a “clinical trial in a dish” (CTIAD) model, using samples from a large, diverse range of sporadic AD patients to build an in vitro AD cohort model. This has led us to our collaboration agreement with StrataStem to commercialize their large-scale collection of AD patient samples as the first step toward an AD CTIAD model. As we continue to develop this concept, we’re also excited to see new insights generated from the StrataStem team.
New insights from the StrataStem Manchester Cohort
Recent work performed by StrataStem on the Manchester patient cohort sought to probe the molecular and cellular mechanisms of early sporadic AD. Led by Chris Ward of StrataStem, in collaboration with the Greater Manchester Dementia Research Centre, the group took iPSCs derived from sporadic AD patient samples and differentiated them into cortical neurons.
These neuronal cultures were then assessed for pathogenic Aß42 peptide secretion, with RNA-sequencing analysis performed to identify pathways associated with early stages of the disease.
The key findings were:
- 60% of AD patient neurons secreted elevated levels of pathogenic Aß42 peptide compared to healthy controls
- 1,112 differentially expressed transcripts were identified in the neurons derived from AD patients, with significant enrichment for genes associated with cilia
- The researchers identified 90 ciliopathic single nucleotide polymorphisms (SNP) within 31 genes, with Aβ42 secretion levels positively correlating with the number of these SNPs
Overall, this points to a potential role for cilia/cytoskeletal dysfunction in the development of sporadic AD, as well as demonstrating the value of assessing large sample collections for iPSC-based AD research.
Click here to find out more about this important work.
Patient stratification in Alzheimer’s Disease models
An AD CTIAD model could transform the drug discovery pathway by accelerating pre-clinical screening, identifying and stratifying best-responders, and de-risking the drug development pipeline. In addition, the models will aid identification of key biomarkers and in stratifying patient cohorts for clinical trials.
We’re now turning our attention to building a consortium to design and execute this CTIAD model. This consortium approach will ultimately help to enhance access, understanding and adoption of the model, driving better outcomes for AD clinical trials.
If you’d like more information, or would like to register interest to join this consortium, please get in contact at operations@axolbio.com
[1] World Health Organization (2023) Dementia (who.int)
[2] Nandi A, Counts N, Chen S, Seligman B, Tortorice D, Vigo D, Bloom DE. Global and regional projections of the economic burden of Alzheimer’s disease and related dementias from 2019 to 2050: A value of statistical life approach. EClinicalMedicine. 2022 Jul 22;51:101580. doi: 10.1016/j.eclinm.2022.101580. PMID: 35898316; PMCID: PMC9310134.
[3] Cummings JL, Feldman HH, Scheltens P. The “rights” of precision drug development for Alzheimer’s disease. Alzheimers Res Ther. 2019 Aug 31;11(1):76. doi: 10.1186/s13195-019-0529-5. PMID: 31470905 PMCID: PMC6717388.
