1. Gluten and Celiac Disease
Ingrid Swanson Pultz, Ph.D.
Institute for Protein Design
University of Washington

2. Gluten is a protein found in wheat, barley, and rye

3. Gluten “Facts” – True or False?

4. Gluten “Facts” – True or False?
Celiac Disease Prevalence is Increasing because of…
True
West et al Am J Gastro 2014; 109:

5. Gluten “Facts” – True or False?
CD Prevalence is increasing because of…
…increased awareness
…increased incidence
CD is
Both
0.2%
0.8%
2009

6. Gluten “Facts” – True or False?
CD is more prevalent because of
genetically-modified wheat

7. Gluten “Facts” – True or False?
CD is more prevalent because of
genetically-modified wheat
False
No GM-wheat is commercially available

8. Gluten “Facts” – True or False?
Gluten can cause symptoms in people without celiac disease

9. Gluten “Facts” – True or False?
Gluten can cause symptoms in people without celiac disease Unclear Non-Celiac Gluten Sensitivity (NCGS)

10. Gluten “Facts” – True or False?
Gluten-free food has no gluten

11. Gluten “Facts” – True or False?
Gluten-free food has no gluten
Not Necessarily True
FDA Mandate of less than 20 PPM

12. Gluten “Facts” – True or False?
Everyone would benefit from a gluten-free diet
False

13. Gluten “Facts” – True or False?
Look, not eating gluten just makes you healthier ok?!
True AND False!

14. Celiac Disease Is a Debilitating Illness
Anemia
Osteoporosis
Malnutrition
Neuropathy
Headache
Neurological
Infertility
Non-Hodgkin’s Lymphoma
Less Common
Classical GI
Dermatitis
Dermatological
Abdominal Pain and Diarrhea

15. Celiac Disease is Characterized by Gluten-Induced Intestinal Damage
Sollid et. al. Nature Immunology 2002

16. The Gluten-Free Diet is Hard
Strict:
Less than mg per day1,2.
Difficult to achieve:
60-70% don’t get there3,4.
Burdensome:
Treatment burden similar to end-stage renal disease5.
Expensive:
Costs 2-3x more; lost productivity
Life-Restricting:
Unwillingness to leave home, inability to attend events, etc.
1Catassi et al. Am J Clin Nutr 2007; 85:160-6
2Akobeng & Thomas. Aliment Pharmacol Ther 2008; 27:
3Midhagen et al. Am J Gastro 2003; 98(9)2023-6
4Hall et al. Appetite 2013; 68:56-62
5Shah et al. Am J Gastro 2014; 109(9):

17. Celiac patients and their doctors have indicated that they would place great value in a therapeutic that could prevent symptoms and intestinal damage upon gluten ingestion

18. Gluten is a protein found in wheat, barley, and rye
Gliadin
Glutenin
a-gliadin
g-gliadin
w-gliadin

19. Gliadin is Difficult for Human Digestive Enzymes to Break Down
Stomach
Intestinal
Inflammation, Symptoms
Toxic
gluten fragment

20. Essential Characteristics of Oral Enzyme Therapeutics for Celiac Disease
Activity in stomach conditions.
Target all immunogenic gluten epitopes.
Reduce gluten to below disease threshold ( mg). ≥99%
Straightforward high-yield production.
Specificity for immunogenic gluten.

21. KumaMax is an Oral Enzyme Therapeutic That Specifically Breaks Down Toxic Gluten Fragments in the Stomach
Gliadin
KumaMax
Stomach
Healthy
Intestines,
Disease Prevented
Non-toxic
gluten fragment
Kuma +

22. KumaMax Design Strategy: 1. Select Template
Kumamolisin from Alicyclobacillus sendaiensis
Engineered Enzyme
Activity in Acidic Conditions
Keep
Easy Manufacturability
Keep
Specificity for PR
Specificity for PQ

23. KumaMax Design Strategy: 2. Computational Redesign
1. Computational design
to increase activity
2. Test designed enzymes
3. Combine promising mutations
KumaMax Lead
Original Kumamolisin

24. KumaMax Degrades All Immunodominant Epitopes from Wheat, Barley, and Rye
33mer Peptide
from a-Gliadin (Wheat)
PQQPIPQ||QPQPYPQ||Q
QPFPQ||QPEQIIPQ||QP
QPFPQPQ||QPFPWQP
Hordein (Barley)
Secalin (Rye)
w-Gliadin (Wheat)

25. KumaMAX Outcomes Drives Down the Immunogenic Gluten Load in Bread
30 Min
10,000 ppm
84.8%
20 ppm
99.97%

26. Reduces Gluten Content in Beer to “Gluten Free” Levels
KumaMAX Outcomes
Reduces Gluten Content in Beer to “Gluten Free” Levels
Gluten Concentration in a Wheat Beer at the Indicated Timepoints After Incubation with Gluten-Degrading Enzymes

27. KumaMAX Outcomes
KumaMax Maintains Substantial Anti-Gluten Activity in the Presence of Significant Amounts of Other Dietary Protein
Control meal (bun only)
Hamburger and Vanilla Shake meal

28. T Cells from Celiacs Don’t Respond to KumaMax-Treated Gluten
KumaMAX Outcomes
T Cells from Celiacs Don’t Respond to KumaMax-Treated Gluten
Gluten Y
T Cell
IFN-g
IFN-g
IFN-g

29. Summary Celiac disease is a debilitating illness
NCGS: more research needed
Certain regions of gliadin trigger celiac disease
KumaMax is a potential treatment

30. Life Sciences Discovery Fund Washington Research Foundation
Acknowledgements
Clancey Wolf
David Baker
Justin Siegel
Christine Tinberg
Chia Heng Lee
Lauren Carter
Sydney Gordon
Sarah Wolf
Elizabeth Stanley
Carmen Gianfrani
Alessandra Camarca
Life Sciences Discovery Fund
Washington Research Foundation