Abstract Details

Title Evaluation of CHIT1 and SERPINA3 as Candidate Cerebrospinal Fluid Biomarkers of Progressive Biology in Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) S33 - Multiple Sclerosis: Biomarkers in MS (3:54 PM-4:06 PM)

Poster/Presentation
Number 003

Background

Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in MS are lacking. Previously, CSF proteomics via data-independent acquisition mass spectrometry identified CHIT1 (activated myeloid cells) and SERPINA3 (reactive astrocytes) as candidate markers putatively reflecting MS progressive biology by associating with slowly expanding lesions (SELs).

Objective

To quantitatively confirm associations between chitotriosidase-1 (CHIT1) or serpin family A member 3 (SERPINA3) and measures of multiple sclerosis (MS) progressive biology and quantitatively assess ocrelizumab treatment effect on cerebrospinal fluid (CSF) levels of these biomarkers.

Design/Methods

CHIT1 and SERPINA3 were measured in CSF from healthy individuals (n=30) and people with relapsing MS (pwRMS; n=79) or with primary progressive MS (pwPPMS; n=22) from the Ocrelizumab Biomarker Outcome Evaluation (OBOE) study (NCT02688985) via enzyme-linked immunosorbent assay. Baseline associations with clinical and magnetic resonance imaging measures were analyzed using Spearman-correlation analysis. Comparisons between pre- vs post-treatment levels were performed using the paired Wilcoxon test.

Results

CHIT1 levels were elevated in pwRMS and pwPPMS, while SERPINA3 levels were elevated only in pwPPMS, vs healthy individuals (all, P<0.05). CHIT1 levels correlated with measures of acute disease activity (T1 gadolinium-enhancing lesions, R=0.33; CSF neurofilament light chain levels, R=0.58) and progressive biology (SEL volume, R=0.38). SERPINA3 levels correlated with progressive biology (SEL volume, R=0.39; CSF glial fibrillary acidic protein levels, R=0.44) (all, P<0.001). Ocrelizumab treatment reduced levels of CHIT1 in pwRMS (median change, −41% [interquartile range {IQR}, −59% to −21%]) and pwPPMS (IQR, −27% [−42% to −17%]) at Week 52 (all, P<0.01). CSF SERPINA3 levels were unaltered following ocrelizumab treatment.

Conclusions

We provide confirmatory evidence for CHIT1 and SERPINA3 as candidate biomarkers of progressive biology in MS. CHIT1 levels were elevated in both pwRMS and pwPPMS and were reduced following ocrelizumab treatment, highlighting CHIT1’s potential role as a treatment response marker of microglial activity in acute and progressive disease.

Authors/Disclosures
Amit Bar-Or, MD, FRCPC (University of Pennsylvania) PRESENTER	Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Genentech. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merk/EMD Serono. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for cabaletta. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck/EMD Serono. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi/Genzyme. The institution of Dr. Bar-Or has received research support from Novartis. The institution of Dr. Bar-Or has received research support from Biogen. The institution of Dr. Bar-Or has received research support from Roche/Genentech.
Jeffrey M. Gelfand, MD, MAS, FAAN (University of California, San Francisco)	Dr. Gelfand has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Arialys. Dr. Gelfand has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ventyx Bio. An immediate family member of Dr. Gelfand has received personal compensation in the range of $50,000-$99,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Headache: The Journal of Head and Face Pain. The institution of Dr. Gelfand has received research support from Genentech/Roche. The institution of Dr. Gelfand has received research support from Vigil Neurosciences. An immediate family member of Dr. Gelfand has received publishing royalties from a publication relating to health care. Dr. Gelfand has received publishing royalties from a publication relating to health care. Dr. Gelfand has received publishing royalties from a publication relating to health care. Dr. Gelfand has a non-compensated relationship as a Trial Steering Committee Chairperson and member with Roche / Genentech that is relevant to AAN interests or activities.
Chinaza Agbim (Genentech, Inc.)	No disclosure on file
H.-Christian C. von Büdingen, MD, FAAN (F. Hoffmann-La Roche Ltd)	Dr. Von Buedingen has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd.. Dr. Von Buedingen has received stock or an ownership interest from F. Hoffmann-La Roche Ltd.
Briana Cameron, PhD (Genentech)	Dr. Cameron has received personal compensation for serving as an employee of Genentech. Dr. Cameron has stock in Genentech.
Ann Herman	Ann Herman has received personal compensation for serving as an employee of Genentech, Inc. Ann Herman has received stock or an ownership interest from F. Hoffman-La Roche Ltd.
Xiaoming Jia, MD, MEng (Genentech)	Dr. Jia has received personal compensation for serving as an employee of Genentech/Roche. Dr. Jia has stock in Roche.
Akshaya Ramesh, PhD	Ms. Ramesh has received personal compensation for serving as an employee of Genentech.
Ryan C. Winger, PhD (Genentech)	Dr. Winger has received personal compensation for serving as an employee of Genentech. Dr. Winger has stock in F. Hoffmann-La Roche Ltd.
Jenny Jiang, none	Mrs. Jiang has nothing to disclose.
Christopher Harp	Christopher Harp has received personal compensation for serving as an employee of Genentech. Christopher Harp has received stock or an ownership interest from Genentech, Inc..
Anne H. Cross, MD, FAAN (Washington University School of Medicine)	Dr. Cross has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Cross has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech / F. Hoffman la Roche. Dr. Cross has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Cross has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for TG Therapeutics. Dr. Cross has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Myers Squibb . Dr. Cross has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Octave. Dr. Cross has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Cross has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Cross has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Cross has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Cross has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squibb. Dr. Cross has received personal compensation in the range of $5,000-$9,999 for serving as an officer or member of the Board of Directors for Consortium of MS Centers. Dr. Cross has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for AAN. The institution of Dr. Cross has received research support from Genentech. Dr. Cross has received intellectual property interests from a discovery or technology relating to health care.

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