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research plan

How to read this page

Start with the article narrative. Use the right sidebar to jump from prose into concept context, nearby graph relationships, and source provenance.

Purpose: Expand the wiki's coverage of the active treatment research landscape beyond what Wikipedia captures. Each section identifies what we currently know, what gaps exist, and specific sources/queries to resolve them.

Status key: ✅ covered in wiki | 🔲 gap to fill | 🔍 specific search needed

Research Priorities (Ordered)

  1. Enzyme therapy (glutenases) — most advanced drug class; several in Phase 2/3
  2. Immunotherapy / tolerance induction — disease-modifying potential (not just symptomatic)
  3. Tight junction modulators — larazotide; mixed Phase 3 results
  4. IL-15 pathway inhibitors — addresses innate immune arm (not just adaptive)
  5. HLA-blocking / T-cell targeting — upstream intervention
  6. Microbiome modulation — environmental modifier; emerging
  7. Refractory celiac disease (RCD) — small patient subset with high mortality; unmet need
  8. Modified / detoxified wheat — long-term food engineering angle
  9. Combination approaches — likely future standard of care

Area 1: Enzyme Therapy (Glutenases)

What we know

Enzymes taken with meals that digest gluten in the GI tract before it crosses the epithelial barrier. Targets prolamins (proline/glutamine-rich; resistant to endogenous proteases).

Known candidates (from Wikipedia, as of 2022)

  • Latiglutenase (ALV003) — combination of EP-B2 + SC-PMP
  • TAK-062 / Kuma030 — engineered glutenase
  • Aspergillus niger prolyl endoprotease (AN-PEP)
  • Endoproptease-40

Gaps 🔲

  • Current Phase 2/3 trial status for each candidate
  • Primary endpoints used (symptom scores? mucosal healing? TTG IgA?)
  • Whether any have reached NDA/approval or been discontinued
  • How AN-PEP differs from prescription candidates (it is sold OTC in some markets)

Search targets 🔍

  • ClinicalTrials.gov: "celiac" AND "glutenase" OR "prolyl endopeptidase"
  • PubMed: "latiglutenase" 2023 2024 2025
  • PubMed: "TAK-062" OR "Kuma030" celiac
  • Takeda pipeline page for TAK-062 status

Area 2: Immunotherapy / Tolerance Induction

What we know

The adaptive immune response to gluten is mediated by HLA-DQ2/DQ8-restricted CD4+ T cells. Inducing tolerance to gluten peptides could be disease-modifying — not just symptom-masking.

Known candidates

  • Nexvax2 (ImmusanT) — intradermal peptide vaccine targeting dominant DQ2.5-restricted gluten epitopes; aimed at inducing regulatory T cell tolerance
  • KAN-101 (Anokion) — oral tolerance induction via liver-targeted antigen delivery

Gaps 🔲

  • Nexvax2 Phase 2 result (a Phase 2 trial reportedly failed ~2019 — confirm and understand why)
  • KAN-101 current trial phase and mechanism details
  • Whether any other vaccine/tolerance approaches are in active development post-Nexvax2 failure
  • How tolerance induction compares mechanistically to allergy immunotherapy (SCIT/SLIT)

Search targets 🔍

  • PubMed: "Nexvax2" OR "ImmusanT" celiac
  • PubMed: "KAN-101" OR "Anokion" celiac tolerance
  • ClinicalTrials.gov: "celiac" AND "tolerance" OR "vaccine"
  • Review paper: search "celiac disease immunotherapy" review 2023 2024

Area 3: Tight Junction Modulators

What we know

Larazotide acetate (AT-1001) — synthetic peptide that tightens intestinal epithelial tight junctions, reducing paracellular gluten permeability. Developed by Alba Therapeutics / 9 Meters Biopharma.

Mechanism: blocks zonulin-mediated tight junction opening (zonulin is upregulated by gliadin).

Gaps 🔲

  • Phase 3 trial results (CeliacShield trial ~2020-2022 — reportedly did not meet primary endpoint)
  • Whether development continues; current regulatory status
  • Whether larazotide has any role as adjunct therapy even if standalone failed
  • Zonulin's broader role — Alessio Fasano's research trajectory

Search targets 🔍

  • PubMed: "larazotide" celiac 2021 2022 2023
  • PubMed: "[zonulin](/pages/zonulin)" [intestinal permeability](/pages/intestinal-permeability) celiac review
  • 9 Meters Biopharma press releases / pipeline
  • Fasano A — recent publications on intestinal permeability

Area 4: IL-15 Pathway Inhibition

What we know (from mechanism.md)

IL-15 activates the innate immune arm of celiac pathogenesis via a shorter gluten peptide (p31–43/49), independent of the adaptive T cell pathway. This is especially relevant in refractory celiac disease (RCD type 2), where aberrant IELs are IL-15-driven.

Known candidates

  • AMG 714 (Amgen) — anti-IL-15 monoclonal antibody; studied in RCD and non-responsive celiac
  • Cendakimab (RVX-002, AbbVie) — IL-33 / eotaxin blocker; also tested in celiac (eosinophilic context)

Gaps 🔲

  • AMG 714 Phase 2 results in RCD type 2 — efficacy and safety data
  • Whether IL-15 inhibition works in non-refractory (standard) celiac disease
  • Status of cendakimab for celiac specifically
  • Other IL-15/IL-15R targeted approaches

Search targets 🔍

  • PubMed: "AMG 714" celiac OR "refractory celiac"
  • PubMed: "[IL-15](/pages/il-15)" celiac treatment 2022 2023 2024
  • ClinicalTrials.gov: "celiac" AND "interleukin-15"
  • Specific newer names noted in recent reviews: CALY-002, TEV-53408, EQ102, EQ302

Area 5: HLA Blocking and T-Cell Targeting

What we know

HLA-DQ2/DQ8 present deamidated gluten peptides to CD4+ T cells — the central adaptive immune event. Blocking this interaction would prevent T cell activation.

Known approaches

  • HLA-DQ2 blockers — small molecules or peptide competitors that occupy the HLA-DQ2 peptide binding groove
  • Anti-CD3 (teplizumab context — studied in T1D, which is comorbid with celiac)
  • JAK inhibitors — broad immunosuppression; studied in RCD

Gaps 🔲

  • Any HLA-DQ2 blocker in clinical trials?
  • JAK inhibitor data specifically in RCD (tofacitinib, ruxolitinib?)
  • TCR-directed therapies in development
  • How the T cell epitope map informs drug design (Sollid group)

Search targets 🔍

  • PubMed: "[HLA-DQ2](/pages/hla-dq2-dq8) blocker" celiac OR "HLA-DQ2 antagonist"
  • PubMed: Sollid celiac T cell epitope 2023 2024
  • PubMed: "JAK inhibitor" refractory celiac
  • ClinicalTrials.gov: "celiac" AND "JAK"

Area 6: Microbiome Modulation

What we know

Environmental risk modifiers for celiac onset include gut microbiome composition, antibiotic use, and infections. The microbiome is altered in celiac patients.

Gaps 🔲

  • Does microbiome composition precede or follow disease onset?
  • Any trials using probiotics, FMT, or microbiome-targeted therapy in celiac?
  • Which specific taxa are depleted or enriched in celiac disease?
  • Does microbiome normalise on GFD?

Search targets 🔍

  • PubMed: "celiac disease" microbiome review 2023 2024
  • PubMed: "celiac" "gut microbiota" probiotic
  • PubMed: Fasano OR Caminero celiac microbiome

Area 7: Refractory Celiac Disease (RCD)

What we know (from terminology.md + management.md)

  • ~1.5% of celiac patients develop RCD
  • Type 1: responds to steroids/azathioprine/budesonide
  • Type 2: aberrant IELs, high EATL risk, treated with cladribine/cyclosporine/SCT

Gaps 🔲

  • Survival data for RCD type 2 with current treatments
  • Whether any emerging therapies (IL-15 blockade, JAK inhibitors, stem cell transplant protocols) are changing outcomes
  • How RCD type 2 is definitionally distinguished from EATL (continuum?)
  • Auto-SCT vs allo-SCT in RCD type 2

Search targets 🔍

  • PubMed: "refractory celiac disease" treatment 2023 2024 2025
  • PubMed: "refractory celiac" stem cell transplant
  • PubMed: "[EATL](/pages/eatl)" enteropathy T cell lymphoma treatment outcomes
  • Review: "refractory celiac" review 2024

Area 8: Modified / Detoxified Wheat

What we know

  • Genetic manipulation to remove immunogenic gliadin epitopes
  • Transamidation — chemical process to render gluten non-immunogenic
  • Sourdough fermentation (Lactobacillus) degrades some (but not enough) gluten

Gaps 🔲

  • Are any low-immunogenic wheat varieties commercially available or in trials?
  • What is the current regulatory status of genetically modified wheat for celiac safety?
  • How far does sourdough fermentation actually get (sufficient for celiac or just reduced-gluten)?
  • Wheat domestication research — which historic varieties are lower in immunogenic epitopes?

Search targets 🔍

  • PubMed: "wheat" "celiac" "epitope" "genetic" 2022 2023 2024
  • PubMed: "sourdough" celiac gluten degradation clinical
  • USDA or EFSA regulatory documents on GM wheat

Synthesis Questions (For Future Q&A Queries)

Once sources are gathered, run these queries against the expanded wiki:

  1. "What is the most likely first approved celiac drug beyond GFD, and what is its mechanism?"
  2. "Why did Nexvax2 fail, and what does that tell us about tolerance induction strategies?"
  3. "What is the treatment algorithm for RCD type 2 in 2025?"
  4. "How does the IL-15 innate pathway relate to the HLA-DQ2 adaptive pathway — are they parallel or sequential?"
  5. "Is there any evidence that combining enzyme therapy + tight junction modulation is more effective than either alone?"
  6. "What does the microbiome data suggest about environmental prevention of celiac disease onset?"

Sources to Acquire for raw/

Priority order for adding to the collection:

PriorityDocumentWhere to Get
1Leffler et al. 2015, "Celiac Disease" NEJM reviewPubMed / NEJM
2Schuppan & Zimmer 2013, "The diagnosis and treatment of celiac disease" DTSCH ARZTEBLPubMed
3ClinicalTrials.gov search export: celiac + interventionalclinicaltrials.gov
4Lastiglutenase Phase 2b results paper (Tye-Din et al. or similar)PubMed
5AMG 714 Phase 2 results paperPubMed
6Fasano A 2020, "All disease begins in the (leaky) gut" reviewPubMed
7Sollid LM 2022 or later — T cell epitope map updatePubMed
8Celiac Disease Foundation "State of Research" annual reportceliac.org
9Kurada et al. 2024 or similar — RCD treatment outcomesPubMed
10Microbiome review 2023+PubMed

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