Assessing Fingolimod Axonal Protection Efficacy in Mouse Optic - - PowerPoint PPT Presentation

Assessing Fingolimod Axonal Protection Efficacy in Mouse Optic Neuritis Using Diffusion Basis Spectrum Imaging (DBSI)

Tsen-Hsuan (Abby) Lin1, Rui-Meng Yang1, Jie Zhan1, Chunyu Song2, Peng Sun1, Michael Wallendorf3, Anne H Cross4,5, and Sheng-Kwei Song1,2,5

1Radiology, 3Biostatistics, 4Neurology, 5The Hope Center for Neurological Disorders,

Washington University School of Medicine, St. Louis, MO , USA

2Biomedical Engineering, Washington University in St. Louis, St. Louis, MO , USA

• Feb. 1st , 2018

ACTRIM, San Diego NAIMS Symposium on Therapeutics

Speaker Name: Tsen-Hsuan (Abby) Lin I have no financial interests or relationships to disclose with regard to the subject matter of this presentation.

Declaration of Financial Interests or Relationships

• Fingolimod is an approved disease-modifying treatment for

relapsing MS.

• Optic neuritis (ON) is often the first clinical sign of MS.
• We employed diffusion basis spectrum imaging (DBSI) to

noninvasively assess the treatment efficacy of fingolimod on EAE mice with ON.

• In vivo DBSI was followed by histological validation.

Introduction

Immunization MOG35-55 EAE

Onset of optic neuritis (10 – 18 days post-immunization)

Day 0

• Saline (n=9)
• Fingolimod

(1 mg/kg, n=8)

….. …..

1 month post- immunization

DBSI Baseline Mice were perfusion fixed after in vivo MRI

2 months post- immunization 3 months post- immunization

DBSI 2 weeks post-treatment DBSI 1 month post-treatment

Fingolimod Treatment Timeline

DBSI 2 months post-treatment

Four DBSI scan time points

• Baseline, one, two, and three months post-immunization

Diffusion Basis Spectrum Imaging (DBSI)* Diffusion Basis Spectrum Imaging (DBSI)

Anisotropic Components Isotropic Components

Cross and Song, Journal of Neuroimmunology 2016; 304: 81-85

MR Imaging Voxel

Baseline 1 Month 2 Months 3 Months

Saline Fingolimod

Non-Restricted (Edema)

Saline Fingolimod

Restricted (Cellularity)

0.4 fraction

Isotropic Components

Baseline 1 Month 2 Months 3 Months

Saline Fingolimod

DBSI λǁ (axonal injury)

Saline Fingolimod

DBSI λ⊥ (demyelination)

2.5 µm2/ms

Anisotropic/Fiber Components

0.8 µm2/ms

Saline Fingolimod

Fiber Fraction (axonal loss)

1.0

Fingolimod Saline 100x Zoom-in 100x Zoom-in

SMI312 (total axons) MBP (myelin) DAPI (cell nuclei)

White bar: 50 μm Yellow bar: 5 μm

Immunohistochemisty (IHC)

SMI31 (Phosphorylated /intact axons)

Histology: Axon Preservation with Fingolimod Treatment

Axonal Integrity Myelination Cellularity Axonal Volume

⋆ ⋆ ⋆

Saline (n=18 nerves) Fingolimod (n=16 nerves)

DBSI Agrees with Histology

Axonal Integrity Myelination Cellularity Axonal Volume Saline (n=18 nerves) Fingolimod (n=16 nerves)

• Fingolimod reduced axonal loss in EAE mouse optic nerve (direct

axonal protection, or indirect protection from its anti-inflammatory effects).

• DBSI could be a non-invasive biomarker to
• monitor disease progression
• assess treatment efficacy
• serve as an outcome measure for MS clinical trials

Conclusions

This work was supported in part by NIH P01-NS059560 (A.H.C.), U01-EY025500(S.- K.S.), Department of Defense Idea Award W81XWH-12-1-0457(S.-K.S.), and National Multiple Sclerosis Society (NMSS) RG 4549A4/1(S.-K.S.), RG 1507-05315 (T.-H.L.).

• Prof. Victor Song
• Prof. Anne H Cross
• Prof. Peng Sun
• Dr. Karen Yang
• Prof. William M Spees
• Dr. Jenny Zhan
• Mr. Bob Mikesell
• Mr. Rob Massa
• Dr. Ajit George

Acknowledgments

Poster Session 1 (P117): Thursday (2/1) 6 – 8 PM

DBSI Agrees with Histology

Axonal Integrity Myelination Cellularity Axonal Volume

Saline (n=18 nerves) Fingolimod (n=16 nerves)

• Visual acuity (VA) for normal C57BL/6 mice: 0.37 ± 0.02 c/d (n = 30)
• Operational definition of onset of optic neuritis: VA ≤ 0.25 c/d (mean – 3 SD)

0.1 0.2 0.3 0.4 0.5 10 20 30 40 50 60

Days post-immunization

Visual Acuity (c/d) Sham (n = 20) EAE (n = 20) Mean ± SD

Onset of Optic Neuritis in MOG35-55 EAE Mice

Lin et al., NeuroImage (2014) 100:244-253 Lin et al., Neurobiology of Disease (2014) 67:1 -8 Chiang et al. NeuroImage (2014) 101:390-398 Lin et al. J of Neuroinflammation (2017) 14(1):78

Onset of optic neuritis  9 – 14 days

Visual Acuity Profile