A Single-cell Platform for Analyzing the Peripheral Immune Response in Alzheimer’s and Alzheimer’s Related Diseases

With this Phase II submission, IsoPlexis will develop an automated system to evaluate the combined peripheral immune response of T cells and monocyte cells to differentiate and monitor neurodegenerative diseases (ND) including Alzheimer’s (AD), Frontotemporal Dementia (FTD), and Multiple Sclerosis (MS). Monitoring disease progression and treatment impact on the immune response currently requires risky Cerebral Spinal Fluid sampling. However, the communication between the central and peripheral immune systems exists and we show it requires a sophisticated single-cell detection system to decipher these interactions from a blood sample. The limited success of current ADRD treatments has led to two key observations: (1) targeting molecular contributors to disease without impacting the inflammatory response or disease progression, or (2) immunotherapy targeting not providing measurably productive outcomes and inducing unfavorable inflammatory side effects. Multiplexed protein biomarkers have proven critical in other human immune therapies (e.g., cancer), drastically improving clinical success and inspiring the extension of this technology towards ADRD. Developing such biomarkers for ADRD requires a technology that (1) measures secreted protein polyfunctionality in a single- cell platform classified by subsets of ADRD peripheral blood cells, (2) isolates sensitive peripheral immune cells necessary to establish correlative biomarker disease profiles, and (3) is able to monitor these emerging biomarkers upon treatment. The IsoPlexis IsoCode’s polyfunctional strength index (PSI), using 30+ secreted proteins per T-cell, has proven to be a correlate of objective response in multiple types of immunotherapies. In a published study on MS patient samples, the IsoPlexis platform has demonstrated a strong stimulatory and inflammatory cytokine secretion profile from monocytes, compared to that of healthy donors, and this secretion profile is greatly reduced upon successful treatment. Initial studies of AD peripheral T cells have shown an increased inflammatory profile relative to age-matched donors driven by unique polyfunctional subsets. With a unique focus on the ND market need, we wish to transition this technology into a fully viable commercial, automated assay system to greatly expedite the industry’s development of ADRD therapies. This Phase II plan enables beta-testing in clinical settings with strong scientific performance history. Aim 1: Develop an automated “flow cell” consumable compartment, which captures ADRD monocytes and T cells in parallel and measures 32- plex single-cell cytokine secretions. Aim 2: Produce a miniaturized, benchtop automated flow cell analysis and workflow system, with cell enrichment module, to provide clinical labs user-friendly sample to answer format. Aim 3: Demonstrate proof-of-concept ability to use IsoPlexis automation at UCI, UCSF and UCONN trials and to profile polyfunctional response of peripheral immune cells in a comparative study of neurodegenerative diseases.Alzheimer’s Disease and related diseases involve neuroinflammation effects that occur while neuronal cells are aberrantly degraded. Taking advantage of the communication between the central immune system in the central nervous system and peripheral blood immune system, IsoPlexis is developing a comprehensive blood-based, biomarker detection system for Alzheimer’s Disease and related diseases. By developing the IsoPlexis automated high-throughput platform to make highly-multiplexed, single-cell measurements that detect and classify proteomic information by different immune cell types will enable researchers and clinicians make precise therapy decisions for a variety of neurodegenerative diseases such as Alzheimer’s Disease, Multiple Sclerosis, and Frontotemporal Dementia.