JAX® In Vivo Services Drug Efficacy Studies: Standard DSS-Induced IBD Protocol

JAX® NOTES Issue 507, Fall 2007

JAX® In Vivo Services uses a series of high-throughput, non-invasive, and highly customizable test platforms to validate drug targets and test drug efficacy on either investigator-supplied mice or any of our over 3,500 JAX® Mice strains, the largest mouse model collection in the world. Our Study Directors collaborate with Jackson Laboratory researchers, putting their unparalleled expertise in mouse disease models to work for you.  We have worked with pharmaceutical, biotech, government, and academic groups on projects ranging from characterizing knockout models to evaluating compound efficacy.

The sample study below describes how the Dextran Sulfate Sodium-induced (DSS-induced) mouse model of inflammatory bowel disease (IBD) is used to screen the suppressive efficacy of novel compounds. The rapid induction of colonic inflammation and predictable progression of symptoms supports low cost, high throughput protocols.
(This is the third in a series of JAX® NOTES articles featuring sample studies performed by JAX® In Vivo Services.)

Base Study Design

This study is designed to answer the question "How well does my test compound suppress intestinal inflammation?" at the lowest possible cost. It is also designed to provide this information in the shortest time possible. Typically, we can complete a study and submit a report to you within 10 weeks of receiving your purchase order and the safety data on your compound.

Either the C57BL/6J (000664) or the BALB/cJ (000651) strain may be used as acute models of IBD. The C57BL/6J strain is highly susceptible and more likely to progress to chronic inflammatory disease. It also requires high doses of reference compound (2mg/mouse glatiramer acetate) to ameliorate IBD symptoms and prevent mortality. The BALB/cJ strain requires less reference compound (1mg/mouse glatiramer acetate) to ameliorate IBD symptoms and prevent mortality (Aharoni et al., 2006. JPET. 318: 68-78.). This sample study uses the C57BL/6J strain.

Thirty-six 7- to 8-week old C57BL/6J mice are imported into JAX® West, West Sacramento, Calif. To facilitate the transfer of enteric flora necessary to induce colitis into these mice, they are co-housed with Il10-deficient mice for 7 days. Then, they are randomly placed in groups according to body weight.

All mice have ad libitum access to drinking water containing 3.5-5% DSS for 5 days.

Treatment

Once-daily dosing begins on day 6 and continues for 7 days. Mice are weighed twice weekly until dosing begins, and daily thereafter (weight loss and subsequent gain profiles are useful indicators of DSS-induced IBD progression).

Mice are observed daily, and clinical measurements, including IBD severity scoring, are conducted twice weekly. The IBD scoring system assigns severity scores of 0-3 for three parameters: stool consistency, fecal blood, and anal prolapse.

Blood is drawn twice: before dosing and at the end of the study.

At the end of the study, colons are harvested, measured, flushed, weighed, and fixed for histopathological analysis and scoring.

Study Timeline

The base study may be expanded to include 2 additional test cohorts, up to a maximum study size of 60 mice.

Deliverables

Blood (serum or plasma)

  • Histology blocks and slides
  • Written report providing the following information: Body weight changes
    Clinical scoring of IBD symptom severity
    Colon lengths and weights
    Histopathology scoring of colons
    Representative data: 3.5 % and 5% DSS-Induced body weight loss.

Figure 4 shows that treatment with 3.5% to 5% DSS results in rapid loss of body weight (15 to 30%, respectively). This marked loss of body weight is a key indicator of onset and severity of DSS-induced colitis.

* Due to the severity of the 5% DSS model, saline is administered on day 10 to combat dehydration; saline administration is not required in the 3.5% DSS model.

To begin the study, we need the following information

Study Specifications:

Preferred Models: C57BL/6J or BALB/cJ Preferred dosing route: ip, po, sc

Vehicle Ð standard vehicles include: saline, PBS,
carboxymethyl cellulose/tween suspension, DMSO

Test compound name and dosing concentration

MSDS for each test compound

Signed Quote

Purchase Order

 

Group

Treatment

Route Option

Schedule

Duration

1

Vehicle

po, ip, sc

daily

7 days

2

Reference compound (commonly used: sulfasalazine, cimetidine)

po, ip, sc

daily

7 days

3

Test compound 1

po, ip, sc

daily

7 days

Figure 1.

Measure

 Day

Total number of
measures per mouse

Body weight

-7, 1, 6-12

11

Blood draw

6, 12

2

Clinical observations

1, 4, 6, 8, 10, 12

6

Colon harvest 12 1

Figure 2.

Figure 3.

Figure 4.