Author Of 2 Presentations
P0102 - KonectomTM smartphone-based digital outcome assessment of cognitive and motor function in multiple sclerosis (ID 815)
Abstract
Background
The next generations of MS therapies aim at enhancing remyelination, protecting neurons/axons and altering the slowly progressive course of MS from its inception. To evaluate their efficacy, it is essential to develop novel, patient-centric outcome assessments that can quantify patient’s function with high frequency in their everyday life.
Objectives
To develop a digital solution that enables patients to quantitatively self-assess their function at high frequency in free-living environment in complement to in-clinic supervised administration and derive outcome measures that are able to detect the subtle changes during MS evolution.
Methods
KonectomTM smartphone application was designed and developed with patient-focused user experience insights to assess cognition, upper extremity function, ambulation/mobility and MS-related quality of life. To optimize accuracy and adherence of self-assessments, tutorials, vocal instructions and completion reward features were built into the app. KonectomTM was developed under IEC 62304 / ISO 13485 standards. KonectomTM digital outcome assessments (DOAs) will derive digital features processed from iPhone X accelerometer, gyroscope, touch, force touch, and GPS sensor information. KonectomTM formal usability study was completed in September 2019, in Chicago and in Paris (N=14 participants). KonectomTM is being evaluated in two Phase 2 studies in patients with relapsing MS (NCT04079088, N=300, 72 weeks of treatment period; undisclosed RMS Ph2 study).
Results
KonectomTM DOAs include 9 active test modules (mood/physical state 5-point Likert scale, multiple sclerosis impact scale 29-item questionnaire version 2 [MSIS-29v2], cognitive processing speed test, pinching test, drawing test, grip force test, static balance test, U-turn test and 6-min walk test) and a passive continuous monitoring of mobility behaviour. In the user experience testing, KonectomTM received a system usability scale (SUS, range 0-100, mean [SD]) score of 87.7 [8.7] which is much above the benchmark average of smartphone applications with a likelihood to recommend (LTR, range 0-10, mean [SD]) of 8.1 [2.0]. Results were consistent between French and US participants.
Conclusions
KonectomTM provides a patient-centric modular digital platform for ecological monitoring of neurological disability in MS clinical trials and real-world use with potential to be extended to other neurological disorders affecting cognitive and motor functions
P0941 - Anti-myelin oligodendrocyte glycoprotein autoantibodies trigger an Fc-Receptor and BTK-dependent proliferative response in microglia (ID 1382)
Abstract
Background
Autoantibodies are a hallmark feature of numerous neurologic disorders, including multiple sclerosis (MS) and Neuromyelitis optica (NMO) even though the exact pathogenic role(s) and mechanism(s) associated with these autoantibodies are not fully understood. Within the CNS, antibodies can bind to both activating and inhibitory Fc-Receptors (FcRs) that are expressed on barrier-associated macrophages, microglia and other trafficking immune subsets. While well understood in peripheral myeloid cells, the pathophysiological significance of autoantibody-induced FcR signaling in microglia remains unknown, in part due to the lack of a robust in vivo model.
Objectives
Develop an in vivo model to assess Fc Receptor (FcR) and Bruton's tyrosine kinase (BTK) dependent antibody-induced microglia activation.
Methods
Anti-Myelin oligodendrocyte glycoprotein (MOG) monoclonal antibodies (mAbs) were generated and injected peripherally. Anti-MOG CNS target engagement and microglia activation were measured by immunohistochemistry and flow cytometry. Microglia transcriptomics were assessed by RNAseq.
Results
Here, we report that peripheral injection of anti-Myelin oligodendrocyte glycoprotein (MOG) monoclonal antibodies (mAbs) triggers a rapid and tightly regulated microglia Ki-67+ proliferative burst in both brain and spinal cord. This microglia activation was FcR-dependent as only Fc effector-competent but not Fc effectorless aglycosylated antibodies triggered the proliferative response. Accordingly, anti-MOG induced microglia proliferation was fully abrogated in FcR knockout mice. The anti-MOG driven microglia proliferative response was associated with a transient and tightly-regulated gene expression signature of largely proliferation-associated genes. Moreover, we determined that anti-MOG-induced microglia activation in vivo was dependent on BTK, a signaling node downstream of FcRs. Specifically, we found that anti-MOG microglia response was amplified in BTKe41K knock-in mice that express a constitutively active form of BTK and was blunted in mice treated with ibrutinib, a CNS penetrant small molecule BTK inhibitor.
Conclusions
Together, these results demonstrate the first report of an in vivo physiological function for FcR and BTK signaling in microglia and we propose that this model provides a novel tool to further dissect the roles of microglia-specific FcR and BTK driven responses to antibodies in CNS homeostasis and disease.