WHY THIS MATTERS
- ►7,000+ rare diseases affect 300 million people globally[1], yet 95% have no approved treatment
- ►80% of rare diseases are genetic in origin, making patient-derived models essential
- ►Patient-derived organoids enable personalized rare disease modeling when clinical trials are impossible
- ►FDA Modernization Act 3.0 now accepts non-animal data, transforming rare disease drug approval
TABLE OF CONTENTS
TRANSFORMING RARE DISEASE RESEARCH
Rare diseases represent one of the most challenging frontiers in medicine. With over 7,000 identified conditions affecting an estimated 300 million people worldwide, these diseases collectively impact more people than cancer and AIDS combined. Yet the economics of drug development have historically made rare diseases unattractive targets: small patient populations mean limited revenue potential, while the cost of bringing a drug to market exceeds $2 billion on average.
Patient-derived organoids and organ-on-chip technologies are fundamentally changing this equation. By enabling drug efficacy testing on patient-specific tissue models, these platforms address the core challenge of rare disease drug development: the impossibility of conducting adequately powered clinical trials when only hundreds or thousands of patients exist globally. The FDA's acceptance of organoid data for drug approval, exemplified by Trikafta's expansion to rare CFTR mutations, signals a paradigm shift that could unlock treatments for thousands of neglected conditions.
THE RARE DISEASE CHALLENGE: WHY TRADITIONAL APPROACHES FAIL
A disease is classified as "rare" when it affects fewer than 200,000 people in the United States or fewer than 1 in 2,000 people in Europe. This definition encompasses a staggering diversity of conditions:
Scale of the Problem
- 7,000+ identified rare diseases with new conditions discovered regularly through genomic sequencing
- 300 million patients globally - approximately 1 in 10 Americans lives with a rare disease
- 80% genetic origin - the majority result from mutations in single genes or chromosomal abnormalities
- 50% pediatric onset - half of rare diseases manifest in childhood, often with devastating consequences
- 30% mortality before age 5 - rare diseases are the leading cause of pediatric mortality[2]
Why Traditional Drug Development Fails
The pharmaceutical industry has historically neglected rare diseases due to fundamental structural challenges:
- Statistical impossibility: Phase III trials typically require 1,000-3,000 patients, impossible when the global patient population may number in the hundreds
- Geographic dispersion: Patients are scattered globally, making recruitment logistically challenging and expensive
- Disease heterogeneity: Even within a single rare disease, patients may carry different mutations with varying phenotypes
- Natural history unknown: Without large patient cohorts, the typical disease progression is often poorly characterized
- Animal model limitations: Many rare human genetic diseases have no adequate animal model, or mouse models fail to recapitulate human pathology
- Economic disincentives: Traditional ROI calculations make rare disease drug development financially unfeasible
The Diagnostic Odyssey
Beyond drug development, rare disease patients face extraordinary diagnostic challenges:
- Average 5-7 year diagnostic journey with multiple misdiagnoses
- 7.3 physicians consulted on average before receiving correct diagnosis
- 40% initially misdiagnosed with a common condition
- $5,000-$30,000 out-of-pocket diagnostic costs for families
ORGANOID-BASED RARE DISEASE MODELING
Organoids offer a revolutionary approach to rare disease research by creating patient-specific tissue models that recapitulate disease pathology at the cellular and molecular level.
How Patient-Derived Organoids Work
The organoid workflow for rare disease applications follows a systematic process:
- Patient sample collection: Tissue biopsy, blood draw, or skin punch biopsy provides starting material
- Cell isolation or reprogramming: Primary cells are isolated or reprogrammed to iPSCs
- Organoid differentiation: Cells are cultured in 3D matrices with growth factors directing organ-specific development
- Disease phenotype validation: Organoids are characterized to confirm they recapitulate disease features
- Drug screening: Candidate therapies are tested for efficacy and safety
- Predictive response assessment: Results inform clinical decision-making for individual patients
Advantages for Rare Disease Research
- Patient-specific genetic background: Organoids carry the exact mutation(s) causing disease
- Unlimited expansion: A single patient sample can generate thousands of organoids for extensive drug screening
- Functional readouts: Organoids enable assessment of tissue function, not just molecular markers
- Human relevance: Eliminates species-specific differences that limit animal model utility
- Scalability: Automation enables high-throughput screening with limited patient material
- Biobanking potential: Organoids can be cryopreserved for future research as new therapies emerge
Organ Systems Successfully Modeled
Rare disease organoid models have been established across virtually every organ system:
- Intestinal organoids: Cystic fibrosis, inflammatory bowel diseases, congenital diarrheal disorders
- Brain organoids: Microcephaly, lissencephaly, Rett syndrome, Huntington's disease
- Liver organoids: Alpha-1 antitrypsin deficiency, Wilson disease, glycogen storage disorders
- Kidney organoids: Polycystic kidney disease, nephronophthisis, Alport syndrome
- Lung organoids: Primary ciliary dyskinesia, surfactant deficiency disorders
- Cardiac organoids: Long QT syndrome, Brugada syndrome, hypertrophic cardiomyopathy
- Retinal organoids: Retinitis pigmentosa, Leber congenital amaurosis, Usher syndrome
iPSC-DERIVED DISEASE MODELS: UNLIMITED PATIENT CELLS
Induced pluripotent stem cell (iPSC) technology has transformed rare disease research by enabling unlimited generation of patient-specific cells from a simple blood draw or skin biopsy.
The iPSC Revolution
Shinya Yamanaka's 2006 discovery that adult cells can be reprogrammed to pluripotency earned the Nobel Prize and opened new frontiers for rare disease research:
- Any cell type accessible: iPSCs can differentiate into neurons, cardiomyocytes, hepatocytes, or any cell type affected by disease
- Patient genetic background preserved: Disease-causing mutations are maintained through reprogramming
- Unlimited supply: iPSCs proliferate indefinitely, providing inexhaustible research material
- Isogenic controls possible: CRISPR correction of disease mutations creates matched healthy controls
iPSC Disease Modeling Workflow
- Patient recruitment: Individuals with confirmed genetic diagnosis provide informed consent
- Sample collection: Peripheral blood mononuclear cells (PBMCs) or dermal fibroblasts obtained
- Reprogramming: Yamanaka factors (Oct4, Sox2, Klf4, c-Myc) delivered via non-integrating methods
- iPSC characterization: Pluripotency markers, karyotype stability, and mutation retention confirmed
- Directed differentiation: iPSCs guided toward disease-relevant cell types using defined protocols
- Disease phenotype validation: Cellular, molecular, and functional disease features confirmed
- Drug screening: Candidate therapeutics tested on patient-derived cells
Major iPSC Repositories for Rare Diseases
- CIRM iPSC Repository: California-funded collection of disease-specific iPSC lines
- WiCell: Distribution center for research-grade iPSC lines
- Coriell Institute: Biobank with rare disease patient samples and derived cell lines
- EBiSC: European Bank for induced pluripotent Stem Cells
- RIKEN BRC: Japanese repository with extensive Asian genetic diversity
CASE STUDIES: ORGANOIDS TRANSFORMING RARE DISEASE TREATMENT
Cystic Fibrosis: The Gold Standard
Cystic fibrosis (CF) organoid research represents the most advanced application of patient-derived models in rare disease drug development. The intestinal organoid swelling assay developed by Hans Clevers' laboratory has become the gold standard for predicting patient response to CFTR modulators.
The Swelling Assay:
- Intestinal organoids from CF patients are exposed to forskolin, activating CFTR-mediated chloride secretion
- Functional CFTR channels cause fluid influx and organoid swelling over 60 minutes
- Dysfunctional CFTR (disease state) results in minimal or no swelling
- CFTR modulators restore swelling in responsive patients
- Swelling response correlates with clinical improvement with >90% accuracy[3]
Regulatory Impact:
- FDA approved Trikafta (elexacaftor/tezacaftor/ivacaftor) for rare CFTR mutations based substantially on organoid swelling data
- Over 2,000 CFTR mutations exist; organoids enable testing of therapies for ultra-rare variants
- Dutch healthcare system uses organoid testing to guide CFTR modulator prescribing
- HIT-CF Europe consortium systematically screening all known CFTR mutations
Huntington's Disease: Brain Organoid Models
Huntington's disease (HD) results from CAG repeat expansions in the huntingtin gene, causing progressive neurodegeneration. Brain organoids from HD patients recapitulate key disease features:
- Mutant huntingtin aggregation: Protein aggregates form in patient-derived organoids as in patient brains
- Neuronal death patterns: Medium spiny neurons show selective vulnerability
- Developmental abnormalities: Organoids reveal early neurodevelopmental defects preceding symptoms
- Drug screening platform: ASO and gene therapy approaches tested in patient-derived tissue
Amyotrophic Lateral Sclerosis (ALS): Motor Neuron Models
ALS research has been transformed by iPSC-derived motor neurons and spinal cord organoids:
- SOD1 mutations: Patient-derived motor neurons show oxidative stress and protein aggregation
- C9orf72 expansions: Most common genetic cause modeled in patient-derived neurons
- TDP-43 pathology: Cytoplasmic TDP-43 aggregation recapitulated in patient organoids
- Drug discoveries: Multiple compounds showing efficacy in patient-derived models advancing to trials
Polycystic Kidney Disease: Kidney Organoid Models
Autosomal dominant polycystic kidney disease (ADPKD) affects 1 in 1,000 people. Kidney organoids from PKD patients enable:
- Cyst formation studies: Patient-derived organoids spontaneously form fluid-filled cysts
- PKD1/PKD2 mutation analysis: Both gene mutations modeled in patient-derived tissue
- Drug screening: Tolvaptan and other therapies tested for cyst-inhibiting efficacy
- Gene therapy development: CRISPR correction approaches validated in organoid models
Retinitis Pigmentosa: Retinal Organoid Models
Retinitis pigmentosa (RP) encompasses over 100 genetic causes of progressive blindness. Retinal organoids enable:
- Mutation-specific modeling: Each genetic subtype can be modeled from patient cells
- Photoreceptor degeneration studies: Disease progression recapitulated in organoid culture
- Gene therapy optimization: AAV-mediated gene delivery tested in patient-derived retinal tissue
- Luxturna precedent: First FDA-approved gene therapy for inherited retinal disease validated in organoid models
GENE THERAPY TESTING IN PATIENT-DERIVED MODELS
For the 80% of rare diseases caused by genetic mutations, gene therapy offers the potential for curative treatment. Patient-derived organoids provide critical platforms for gene therapy development and optimization.
Gene Therapy Modalities Tested in Organoids
- AAV gene addition: Adeno-associated virus vectors delivering functional gene copies tested for tropism, expression levels, and duration
- CRISPR gene correction: Precise editing of disease-causing mutations with assessment of on-target efficiency and off-target effects
- Base editing: Single nucleotide corrections without double-strand breaks validated in patient cells
- Prime editing: Versatile editing approach for insertions, deletions, and substitutions tested in organoid models
- Antisense oligonucleotides: Splice-modulating and expression-reducing ASOs screened for efficacy
- mRNA therapeutics: Transient protein expression approaches evaluated in patient tissue
Critical Safety Assessments
Organoids enable comprehensive safety evaluation before clinical application:
- Off-target editing analysis: Whole-genome sequencing of edited organoids identifies unintended modifications
- Chromosomal stability: Karyotyping ensures editing doesn't cause chromosomal aberrations
- Functional restoration: Confirmation that genetic correction restores normal cellular function
- Immune response evaluation: Assessment of immunogenicity in patient-derived immune organoids
- Long-term stability: Extended culture confirms durability of genetic correction
Successful Gene Therapy Applications
- Luxturna (voretigene neparvovec): RPE65-associated retinal dystrophy treatment validated in retinal organoids
- Zolgensma (onasemnogene abeparvovec): SMA gene therapy with organoid-supported development
- Casgevy (exagamglogene autotemcel): CRISPR therapy for sickle cell disease validated in patient-derived models
- CTX001: Beta-thalassemia gene editing therapy with extensive organoid testing
REGULATORY PATHWAYS FOR RARE DISEASE THERAPIES
Regulatory agencies worldwide have created expedited pathways for rare disease drug development, increasingly accepting organoid and organ-on-chip data as supporting evidence.
FDA Rare Pediatric Disease Priority Review Voucher
The Rare Pediatric Disease Priority Review Voucher (PRV) program provides powerful incentives:
- Voucher award: Sponsors of approved rare pediatric disease treatments receive a PRV
- Transferable value: PRVs can be sold for $100M+ to expedite any FDA review
- Review acceleration: Standard 10-month review reduced to 6 months
- Organoid evidence: Patient-derived organoid data increasingly supports PRV applications
Orphan Drug Act Incentives
The 1983 Orphan Drug Act created the foundation for rare disease drug development:
- 7-year market exclusivity: Protection from generic competition after approval
- 25% tax credit: Clinical trial costs qualify for tax credits
- Waived FDA fees: Application fees eliminated for orphan drugs
- Protocol assistance: FDA provides guidance on development programs
- NAMs integration: Organoid data increasingly accepted in Orphan Drug applications
FDA Modernization Act 3.0 Impact
The 2022 FDA Modernization Act 3.0 removed the animal testing requirement, creating new opportunities:
- Non-animal methods accepted: Organoids and organ-on-chip can replace animal studies
- Rare disease relevance: Particularly valuable when no adequate animal model exists
- Regulatory guidance: FDA developing frameworks for organoid data submission
- Qualification pathway: Organoid assays can be qualified as Drug Development Tools
EMA PRIME Designation
European Medicines Agency Priority Medicines (PRIME) scheme supports rare disease development:
- Enhanced interaction: Early dialogue with EMA scientific committees
- Accelerated assessment: 150-day review timeline vs. standard 210 days
- Organoid evidence: EMA accepts organoid data for efficacy demonstration
- Conditional approval: Earlier access based on preliminary evidence including organoid data
International Harmonization
- ICH guidelines: International Council for Harmonisation developing organoid guidance
- Japan PMDA: Sakigake designation accepts innovative methodologies including organoids
- Health Canada: Priority review pathway accepts NAM evidence for rare diseases
- TGA Australia: Orphan drug pathway integrating organoid evidence
N-OF-1 TRIALS: PERSONALIZED RARE DISEASE TREATMENT
For ultra-rare diseases affecting only dozens or hundreds of patients globally, traditional clinical trials are impossible. N-of-1 trials represent a paradigm shift enabled by patient-derived organoids.
What Are N-of-1 Trials?
N-of-1 trials are clinical studies where a single patient serves as their own control:
- Individual as study population: The patient both receives treatment and serves as control
- Crossover design: Alternating treatment and placebo periods within the same patient
- Objective measurement: Quantitative endpoints measured repeatedly over time
- Statistical validity: Multiple treatment periods enable within-patient statistical analysis
Organoids Enable N-of-1 Evidence Generation
Patient-derived organoids transform N-of-1 trial feasibility:
- Pre-treatment prediction: Drug efficacy tested in patient's own organoids before administration
- Dose optimization: Optimal dosing determined in organoid models to maximize efficacy and minimize toxicity
- Combination screening: Multiple drug combinations tested simultaneously in patient organoids
- Regulatory evidence: Organoid data supplements limited clinical evidence for approval
Milasen: The First N-of-1 Drug
The Milasen case demonstrates the potential of individualized rare disease treatment:
- Patient: Mila Makovec, a child with Batten disease caused by a unique mutation
- Timeline: Diagnosis to treatment in under 12 months
- Approach: Custom antisense oligonucleotide designed for her specific mutation
- Validation: Patient-derived cell models used to confirm therapeutic efficacy
- Outcome: Seizure frequency reduced from 30/day to near zero
- Regulatory precedent: FDA allowed compassionate use based on individualized evidence
Challenges and Considerations
- Cost: Individualized drug development costs $1-3 million per patient
- Timeline: Even accelerated development requires 6-12 months
- Manufacturing: GMP production for single patients is resource-intensive
- Reimbursement: Insurance coverage for N-of-1 treatments remains uncertain
- Sustainability: Scaling individualized approaches requires new models
BIOBANKING PATIENT-DERIVED CELLS FOR RARE DISEASE RESEARCH
Biobanks of patient-derived cells and organoids are essential infrastructure for rare disease research, enabling drug development even when individual patient populations are too small for traditional approaches.
Major Rare Disease Biobanks
- Cystic Fibrosis Foundation Therapeutics Lab: Intestinal organoids from >500 CF patients covering rare CFTR mutations
- HUB Organoids: Commercial biobank with patient-derived organoids for multiple rare diseases
- Coriell Institute: >250,000 cell lines including extensive rare disease collection
- NINDS Human Cell Repository: Neurological disease patient cells and iPSC lines
- UK Biobank: Population-scale resource with rare disease phenotype data
- CIRM iPSC Repository: California-funded collection emphasizing genetic diversity
Biobank Operations
Effective rare disease biobanking requires:
- Patient recruitment: Partnership with patient advocacy groups and clinical centers
- Informed consent: Broad consent enabling future research applications
- Sample processing: Standardized protocols for cell isolation and cryopreservation
- Quality control: Rigorous characterization of genetic and phenotypic features
- Data management: Linked clinical and molecular data with appropriate de-identification
- Access policies: Clear frameworks for researcher access balancing openness and protection
Patient Advocacy Role
Patient advocacy organizations drive rare disease biobanking:
- Cystic Fibrosis Foundation: Pioneered patient-driven biobanking model
- Parent Project Muscular Dystrophy: Funds DMD biobank development
- ALS Association: Supports motor neuron iPSC banking
- NORD (National Organization for Rare Disorders): Coordinates cross-disease biobanking efforts
- Patient-led biobanks: Emerging model with patients controlling their own samples
TRADITIONAL VS. ORGANOID-BASED RARE DISEASE RESEARCH
| Aspect | Traditional Approach | Organoid-Based Approach |
|---|---|---|
| Disease Model | Animal models (often inadequate for human genetic diseases) | Patient-derived tissue with exact disease-causing mutations |
| Sample Requirements | Large patient cohorts for clinical trials | Single patient sample expandable indefinitely |
| Drug Screening Capacity | Limited by animal availability and cost | High-throughput screening of thousands of compounds |
| Patient Specificity | Population-level predictions only | Individual patient response prediction |
| Mutation Coverage | One animal model per mutation (impractical) | Any patient mutation can be modeled directly |
| Time to Results | Years for clinical trial recruitment and execution | Weeks to months for organoid-based screening |
| Cost per Patient | $50,000-$150,000 clinical trial cost per patient | $5,000-$15,000 for complete organoid workup |
| Regulatory Acceptance | Established but often impossible to execute | Increasingly accepted (Trikafta precedent) |
| Gene Therapy Testing | Animal models may not predict human response | Direct testing in patient cells with disease mutation |
| Ultra-Rare Disease Feasibility | Essentially impossible (<100 patients globally) | Feasible with N-of-1 organoid-guided approach |
INDUSTRY LEADERS IN RARE DISEASE ORGANOID RESEARCH
Pharmaceutical Companies
- Vertex Pharmaceuticals: Pioneered CF organoid-guided drug development; Trikafta generated $8.9B revenue in 2023
- Sarepta Therapeutics: DMD gene therapy programs utilize patient-derived muscle models
- BioMarin: PKU and rare metabolic disease programs incorporate organoid screening
- Ultragenyx: Rare disease focus with organoid-supported development pipelines
- Alexion/AstraZeneca: Complement-mediated rare diseases modeled in patient organoids
Technology Providers
- HUB Organoids: Commercial organoid biobank with rare disease collections
- Emulate: Organ-on-chip platforms adapted for rare disease modeling
- MIMETAS: OrganoPlate technology for rare disease drug screening
- Recursion: AI-powered rare disease drug discovery using cellular imaging
- Insitro: Machine learning-driven rare disease target identification
Academic Centers of Excellence
- Hubrecht Institute (Netherlands): Hans Clevers lab developed foundational organoid technology
- Harvard Stem Cell Institute: iPSC disease modeling across rare diseases
- Stanford Institute for Stem Cell Biology: Rare blood and immune disease models
- Cincinnati Children's: Pediatric rare disease organoid programs
- University of Cambridge: Liver and intestinal rare disease organoids
Patient Advocacy Partnerships
- CF Foundation + Vertex: Model partnership generating transformative therapies
- PPMD + Industry: Duchenne MD organoid research funding
- NORD Coalition: Cross-disease collaboration on biobanking and research
- Global Genes: Rare disease advocacy network supporting organoid research
FREQUENTLY ASKED QUESTIONS
Rare diseases are conditions affecting fewer than 200,000 people in the US (or 1 in 2,000 in Europe). Over 7,000 rare diseases exist, 80% are genetic in origin, and 95% have no FDA-approved treatment. Traditional research is challenging due to small patient populations making clinical trials impractical, limited disease understanding, geographic dispersion of patients, and inadequate animal models for human genetic conditions. The average rare disease patient waits 5-7 years for diagnosis and sees over 7 physicians before receiving a correct diagnosis.
Organoids enable patient-specific disease modeling by creating miniature organ structures from patient cells. This allows researchers to test drug efficacy on tissue carrying the exact genetic mutation causing the disease, predict individual patient responses before treatment, screen thousands of compounds with limited patient samples, and support regulatory approval with functional evidence when large clinical trials are impossible. A single patient sample can be expanded to generate thousands of organoids for extensive screening.
The CF organoid swelling assay measures CFTR channel function by exposing intestinal organoids to forskolin, which activates chloride transport. Functional CFTR causes organoids to swell with fluid; dysfunctional CFTR results in no swelling. This assay predicts patient response to CFTR modulators with over 90% accuracy and was instrumental in FDA approval of Trikafta for rare CFTR mutations. The assay can test any of the 2,000+ known CFTR mutations to identify which patients will respond to specific therapies.
N-of-1 trials are individualized clinical studies where a single patient serves as their own control. Organoids enable N-of-1 trials by providing patient-specific tissue for drug testing, allowing comparison of treatment responses in the patient's own cells before administration, and generating evidence for regulatory approval when traditional trials with multiple patients are impossible due to ultra-rare disease prevalence. The Milasen case demonstrated this approach, delivering a custom antisense oligonucleotide to a single patient with a unique Batten disease mutation.
The FDA Rare Pediatric Disease Priority Review Voucher (PRV) program incentivizes development of treatments for rare pediatric diseases by awarding a voucher that can be used or sold (for $100M+) to expedite FDA review of any future drug application. The voucher reduces standard 10-month review to 6 months. Organoid data supporting drug efficacy in rare pediatric conditions can contribute to PRV eligibility, providing significant financial incentive for rare disease drug development.
Patient-derived cells are biobanked through collection of tissue samples (skin biopsies, blood), reprogramming to iPSCs for unlimited expansion, cryopreservation in liquid nitrogen, and cataloging with detailed phenotypic and genetic data. Major biobanks like the Cystic Fibrosis Foundation Therapeutics Lab and HUB Organoids maintain collections covering hundreds of rare disease mutations for research access. These biobanks enable drug development even when individual patients cannot be recruited for clinical trials.
Organoids serve as critical platforms for gene therapy development by testing CRISPR gene correction efficiency and safety, evaluating AAV vector delivery and expression, screening for off-target effects before clinical application, and demonstrating functional restoration of disease phenotypes. This is particularly valuable for rare genetic diseases where the causative mutation is known. Successful gene therapies including Luxturna (retinal dystrophy) and Zolgensma (SMA) were validated in organoid models before clinical application.
The Orphan Drug Act (1983) provides incentives for rare disease drug development including 7 years market exclusivity, 25% tax credits for clinical research, and waived FDA application fees. Organoid-based evidence increasingly supports Orphan Drug applications by demonstrating drug efficacy in patient-derived tissue models when traditional clinical evidence is limited by small patient populations. The FDA Modernization Act 3.0 (2022) further enables organoid data submission by removing the animal testing requirement.
Organoid models have demonstrated high predictive accuracy across multiple disease areas. The cystic fibrosis organoid swelling assay predicts patient response to CFTR modulators with >90% accuracy. Cancer organoid drug screening shows 80-90% concordance with patient clinical responses. The accuracy depends on the disease model maturity, assay development, and extent of validation studies. Ongoing efforts focus on standardizing protocols and conducting prospective validation studies to further establish predictive accuracy.
Organoid-based research costs vary by application. iPSC generation and characterization costs $15,000-$30,000 per patient line. Organoid differentiation and disease modeling adds $5,000-$15,000. Drug screening campaigns range from $50,000-$500,000 depending on throughput. Compared to clinical trial costs ($50,000-$150,000 per patient), organoid approaches offer significant cost advantages, particularly for rare diseases where patient recruitment is challenging. N-of-1 individualized drug development costs $1-3 million but may be the only option for ultra-rare conditions.
References
- Global Genes (2024). RARE Facts. GlobalGenes.org
- Nguengang Wakap S, et al. (2020). Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. European Journal of Human Genetics, 28, 165-173. DOI: 10.1038/s41431-019-0508-0
- Dekkers JF, et al. (2016). A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nature Medicine, 19(7), 939-945. DOI: 10.1038/nm.3201