Progressive multifocal leukoencephalopathy: biomarkers for early diagnosis, risk assessment of immunotherapies, and response to targeted therapy

• Applicants: Dr. Steffi Silling; Professor Dr. Jörg Timm, since 10/2023; Professor Dr. Clemens Warnke
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Virology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 501362249

Progressive multifocal leukoencephalopathy (PML) is a serious condition caused by human polyomavirus 2 (HPyV-2, commonly referred to as JC polyomavirus (JCPyV)). Lytic infection of brain cells causes neurological deficits that are often progressive and result in death or severe neurologic disabilities in those who survive. PML particularly occurs in AIDS-patients and those with haemato-oncological disease. Another risk group are patients with autoimmune disease, receiving immunosuppressive therapies. HPyV-2 causes an asymptomatic infection in 50-70% of the adult population. Modifications to the viral genome in various gene regions have been identified as an important pre-requisite for the development of PML. It is, however, still unclear where those viral gene modifications initially arise. In this context, HPyV-2 infected cells in renal tissue, of blood cells or epithelial cells of the gut might play a role, and tissue-specific genetic variations could be monitored to assess the individual risk of PML.When clinical examination leads to the suspicion of PML and magnetic resonance imaging (MRI) shows compatible findings, diagnosis is confirmed by the detection of HPyV-2 DNA in cerebrospinal fluid (CSF). However, in about 20% of PML patients HPyV-2 detection fails at the first attempt when performed in commercial laboratories in Germany, possibly delaying the diagnosis of PML in every 5th case. To date, no HPyV-2 directed approved therapy for PML is available, and management is restricted to supportive measures and restoring HPyV-2-specific immune functions. Recently, several targeted therapy approaches have been proposed. However, appropriate study endpoints and standardized methods to evaluate the response to therapy are still missing.Therefore, we pursue the following goals:• Improvement of methods for early PML diagnosis. Pre-analytically, extracellular vesicles are to be enriched and improved methods for virus detection (DNA) are to be applied.• Evaluation of tissue-specific viral genetic changes may allow personalized PML risk prediction.• Development of surrogate marker for HPyV-2-specific immune competence (neutralizing antibody responses, T-cell responses), which can be used as endpoints in clinical studies.Our work will be of direct clinical relevance, improving diagnostic care as well as PML risk assessment. Characterization of HPyV-2-specific antibody and T-cell responses will lead to the development and validation of surrogate marker. Those will be essential for therapeutic clinical studies, assessing e.g. the efficacy of HPyV-specific T-cells or broadly neutralizing antibodies to be used for the therapy of PML. The project will benefit from a regular exchange of ideas with PML experts in Germany and the US.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Ortwin Adams, until 9/2023 (†)