2025 American Academy of Neurology Abstract Website

Objective:

In this preclinical study, we aim to investigate the therapeutic potential of an antisense oligonucleotide (ASO) targeting CD49d in the context of autoimmune encephalitis (AE). Through suppression of T-cell signaling, ASO to CD49d could mitigate the immune mediated neuroinflammation.

Background:

AE encompasses disorders with autoimmune blockade of neural signaling leading to epilepsy, including Hashimoto’s and Rasmussen’s encephalitis (RE). Many AE patients do not respond to treatments. RE, a rare AE, manifests as focal encephalitis that affects children, adolescents and adults with 20-30% resistant to treatments. ATL1102 is an ASO to the CD49d alpha-subunit of VLA-4 lymphocyte adhesion molecule reduces inflammatory brain lesions in multiple-sclerosis.

Design/Methods:

FVB male mice (n=20/group) were dosed once weekly for 7 weeks, with either 20mg/kg/week ASO to mouse CD49d (ISIS348574), negative control mismatch oligonucleotide (MM) or saline starting 2 days before seizure induction with 315mg of pilocarpine. Onset to status epilepticus (SE) and SE severity were assessed for 120 minutes post induction. Mice were then recorded for spontaneous recuring seizures (SRS) 8hrs daily, days 31-46 post SE, and seizure duration, severity and frequency assessed blinded.

Results:

ASO to CD49d delayed SE onset versus MM (37%, p=0.0237) and pooled saline+MM controls (26%, p=0.0166) and reduced SE severity versus saline over 90-120 minutes after SE onset (p=0.0072). ASO delayed median SRS frequency versus saline on days 31-32 (100%, p=0.0019) and onset 3 days vs saline (p=0.0041). ASO reduced median SRS frequency versus both saline and MM from days 31-38 (54%, p=0.0868, 53%, p=0.0256), days 31-43 (66%, p=0.0307, 55%, p=0.0258) and days 31-46 (45%, p=0.0508, 54%, p=0.039) six days past last dose, and versus pooled saline+MM controls (p=0.0256, p=0.0096, p=0.0182) respectively.

Conclusions:

This is the first study with ASO to CD49d in mouse pilocarpine AE models and support potential use of ATL1102 in RE and AE patients resistant to current treatments.