Abstract Details

Title Polymerase I Pathway Inhibitor Ameliorates Experimental Autoimmune Encephalomyelis

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 173

Objective

Background BACKGROUND: Applying high throughput gene expression microarrays, we have identified that suppression of polymerase I (Pol I) pathway was associated with the benign course of MS. This finding supports the rational for direct targeting of Pol I transcription machinery as an innovative strategy to suppress MS.

Design/Methods DESIGN/METHODS: EAE was induced in female C57BL/6J mice (8 weeks) by subcutaneous immunization with MOG35-55/CFA. The specific Pol I inhibitor CX-5461 compound was synthesized according to published procedure (www.cylenepharma.com/pipeline/pol-i-program) and administered at a daily dose of 12.5mg/kg body weight by oral gavage either from the day of immunization until disease onset (EAE score 1.0, immunization model, n=10), or at disease onset (EAE score 1.0) for the following 14 days (treatment model, n=10). Mice were monitored daily for clinical signs of EAE, and scored a follows: 1=flaccid tail; 1.5=hind limb weakness; 2=paralyzed hind limb and poor righting ability; 2.5=forelimb weakness, paralyzed hind limb, and paralyzed tail; 3=four limbs paralysis, inability to right; 4=quadriplegia. Disease progression parameters were compared between CX5461 treated mice and vehicle treated controls (n=10 for each treatment group).

Results RESULTS: CX5461 remarkably suppressed EAE in the immunization model. While in the vehicle group the onset of EAE occurred on day 11.7±1.4 with maximal clinical score of 3.7±0.7, in the CX5461 treated mice onset was significantly delayed and occurred on day 20.8±1.4 (p=0.002), and maximal disease score 2.8±0.5 was reduced (p=0.02). In the treatment model CX5461 treatment also significantly reduced disease activity; maximal score was 2.0±0.5 while in the vehicle group it reached a mean maximal score of 4.4±0.2, (p=0.0004).

Conclusions CONCLUSIONS: Pol I pathway inhibition delayed and suppressed the development of EAE and ameliorated the disease in mice with persistent clinical signs.

Authors/Disclosures
Anat Achiron, MD, PhD, FAAN (Sheba Medical Center, Tel-Hashomer) PRESENTER	Dr. Achiron has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Zachary Grinspan, MD	Dr. Grinspan has received personal compensation for serving as an employee of Weill Cornell Medicine. Dr. Grinspan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alpha Insights. Dr. Grinspan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biopharma LTD (South Korea). Dr. Grinspan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Encoded Therapeutics. The institution of Dr. Grinspan has received research support from SLC6A1 Connect. The institution of Dr. Grinspan has received research support from STXBP1 Foundation. The institution of Dr. Grinspan has received research support from Clara Inspired. The institution of Dr. Grinspan has received research support from Amgen. The institution of Dr. Grinspan has received research support from NINDS. Dr. Grinspan has received intellectual property interests from a discovery or technology relating to health care.
Michael Gurevich (Sheba Medical Center)	No disclosure on file

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