Development of a topical tracer to detect TDP43 in ALS, LATE and FTD retinas for AI-powered disease insights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the pathological accumulation of TDP-43 in the cytoplasm, disrupting normal cellular functions. TDP-43 deposits are also a hallmark of frontotemporal dementia (FTD), which is etiologically linked to ALS, and limbic-predominant age- related TDP-43 encephalopathy (LATE), a common cause of dementia that is often a co-morbid feature of Alzheimer’s disease. Currently, no methods exist to clinically detect and quantify TDP-43 pathology as a disease biomarker, which delays diagnosis and treatment. Development of new technologies to detect TDP-43 pathology in central nervous system (CNS) tissue would have a transformative impact on the early diagnosis of ALS, FTD, and LATE, while also aiding in the identification of LATE/TDP-43 pathology as a component of mechanistic heterogeneity in neurodegenerative conditions such as Alzheimer’s typically defined by other biomarkers. It could also help differentiate between FTD-TDP-43 and FTD-Tau, each of which accounts for nearly 50% of cases and may benefit from distinct interventions. A TDP-43 biomarker test could also enhance the clinical development of new precision medicine interventions for ALS and other diseases and guide their use. The presence of TDP-43 in the retina presents a unique opportunity for non-invasive detection of ALS and other TDP-43-related diseases. As an accessible part of the CNS, the retina serves as a "window to the brain" that harbors neural, synaptic, and glial elements affected by neurodegenerative diseases. Importantly, deposits of protein biomarkers, such as amyloid β in Alzheimer's disease and α-synuclein in Parkinson's disease, form in retina as they do in brain, correlating across tissues. Amydis has developed first-in-class fluorescent retinal tracers to non-invasively label disease-related biomarkers in the retina for detection with standard retinal imaging systems already part of patient care. With Phase 1 NIH funding, Amydis demonstrated that its novel tracers label cytoplasmic TDP-43 deposits in ALS human cadaver retina, spinal cord, and motor cortex. Further studies showed that our tracers label TDP-43 in FTD and LATE. These findings suggest that Amydis tracers could enable the first non-invasive detection of TDP-43 in ALS, FTD, and LATE, representing a breakthrough in early diagnosis, treatment, and monitoring of these diseases. In this Phase 2 project, we propose 3 aims to lay the foundation for clinical trials of our tracer technology in ALS and other TDP-43 proteinopathies. Aim 1 will characterize patterns of retinal TDP-43 deposition in ALS, FTD, and LATE compared to healthy controls using the clinical lead tracer, AMDX- 2011P. Aim 2 will build a TDP-43 retinal imaging database and accompanying computer vision software and AI- powered analytics to automatically delineate and quantify tracer labeled TDP-43 deposits. Aim 3 will develop a topical formulation of AMDX-2011P to expand patient access to testing. Success in these aims will provide data on retinal TDP-43 pathology critical to designing clinical imaging protocols, software to help physicians (in trials and at point of care) interpret tracer signals for diagnosis and monitoring, and a formulation that can be readily used by eyecare professionals and other providers.