5 hypotheses
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8 open gaps
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0 live debates
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0 tokens funded
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3/7 hub

What we know

  • 5 active hypothesises in scope
  • 8 open frontiers with evidence gaps
  • 10 indexed papers in corpus
5 hypotheses in scope top ranked
11 open frontiers
0 in-flight debates
0 tokens funded

Top hypotheses

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  1. #1 AAV-PHP.eB-Mediated Microglial IGFBPL1 Expression 77% proposed IGFBPL1 PMID:31932725PMID:31235620 +6 refs
  2. #2 Focused Ultrasound with Microbubble Contrast Agents 68% proposed IGFBPL1 PMID:28847786PMID:30542028 +6 refs
  3. #3 Fusing IGFBPL1 to IGF-1 for Receptor-Mediated BBB Transcytosis 55% proposed IGFBPL1 PMID:7559877PMID:17698609 +1 refs
  4. #4 Lipid Nanoparticle Encapsulation of IGFBPL1-mRNA 53% proposed IGFBPL1 PMID:33139562PMID:34522186 +1 refs
  5. #5 Intranasal IGFBPL1 Delivery via Olfactory Pathway 46% proposed IGFBPL1 PMID:29353687PMID:16828543 +1 refs

Open frontiers

All gaps →
How can specialized pro-resolving mediators be effectively delivered across the blood-brain barrier?

SPM enhancement shows high therapeutic potential but faces critical delivery challenges that previous pharmaceutical efforts failed to solve. The debate identified this as a major feasibility barrier but provided no viable solutions for CNS targeting. Source: Debate session sess_sda-2026-04-01-gap-009 (Analysis: sda-2026-04-01-gap-009)

priority 71%
Can lipid nanoparticles achieve true astrocyte-selective delivery in the CNS?

Multiple hypotheses relied on cell-type specific targeting, but the debate revealed uncertainty about whether current delivery technologies can achieve this selectivity. The feasibility of selective targeting determines whether these therapeutic approaches are viable. Source: Debate session sess_SDA-2026-04-03-gap-debate-20260403-222543-20260402 (Analysis: SDA-2026-04-03-gap-debate-20260403-222543-20260402)

priority 80%
What CNS penetration strategies can achieve therapeutic concentrations of proteostasis enhancers?

The domain expert noted poor CNS penetration of existing autophagy enhancers like rapamycin, but alternative delivery methods weren't explored. This pharmacokinetic barrier represents a major obstacle to translating proteostasis-based therapies. Source: Debate session sess_SDA-2026-04-01-gap-012 (Analysis: SDA-2026-04-01-gap-012)

priority 69%
Can nanobodies achieve blood-brain barrier penetration while maintaining tau-binding specificity and membrane activity?

The domain expert flagged BBB penetration as a major limitation for CNS nanobodies, but the debate didn't resolve whether membrane-active modifications compromise BBB transport or tau binding. This represents a critical feasibility bottleneck. Source: Debate session sess_SDA-2026-04-10-SDA-2026-04-09-gap-debate-20260409-201742-ca7016f1 (Analysis: SDA-2026-04-09-gap-debate-20260409-201742-ca7016f1)

priority 85%
Can engineered protein scaffolds cross the blood-brain barrier without disrupting endogenous networks?

Multiple experts highlighted delivery challenges and potential toxicity from artificial scaffolds sequestering normal proteins. The feasibility of CNS delivery while maintaining selectivity for disease-affected interactions remains experimentally unresolved. Source: Debate session sess_SDA-2026-04-08-gap-pubmed-20260406-062222-cc3bcb47 (Analysis: SDA-2026-04-08-gap-pubmed-20260406-062222-cc3bcb47)

priority 75%
What specific mechanisms enable EVs to cross the blood-brain barrier while other therapeutics cannot?

The abstract states EVs have 'intrinsic ability to cross the BBB' but doesn't explain the underlying mechanisms. Understanding these mechanisms is crucial for optimizing EV-based therapeutics and potentially engineering other BBB-crossing delivery systems. Gap type: unexplained_observation Source paper: Therapeutic potential of extracellular vesicles in neurodegenerative disorders. (2023, Handbook of clinical neurology, PMID:36803815)

priority 80%
What are the key challenges limiting EVs as effective drug delivery vehicles for neurodegeneration?

The abstract mentions that challenges exist for using EVs as delivery vehicles but doesn't specify what these limitations are. Identifying these barriers is essential for advancing EV-based therapeutics from research to clinical application. Gap type: open_question Source paper: Extracellular vesicles: biological mechanisms and emerging therapeutic opportunities in neurodegenerative diseases. (2024, Translational neurodegeneration, PMID:39643909)

priority 82%
How does intranasal delivery achieve preferential targeting to peri-infarct regions versus healthy brain tissue?

The study shows increased circSCMH1 distribution in peri-infarct regions via intranasal delivery, but the mechanism for this selective targeting is unexplained. This knowledge gap limits optimization of delivery strategies and understanding of nose-to-brain transport in stroke conditions. Gap type: unexplained_observation Source paper: Nose-to-Brain Delivery of Circular RNA SCMH1-Loaded Lipid Nanoparticles for Ischemic Stroke Therapy. (2025, Advanced materials (Deerfield Beach, Fla.), PMID:40143778)

priority 75%

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