Evidence map›Paper›PMID 41267399›Full record

ArticleMolecular therapy : the journal of the American Society of Gene Therapy2026

Haplotype editing with CRISPR-Cas9 as a therapeutic approach for dominant-negative missense mutations in NEFL.

Poorvi H Dua, Bazilco M J Simon, Chiara B E Marley, Carissa M Feliciano, Hannah L Watry, Quinn T Cowan, Dylan Steury, Abin Abraham, Erin N Gilbertson, Grace D Ramey and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors.

Poorvi H DuaDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA.
Bazilco M J SimonGladstone Institutes, San Francisco, CA 94158, USA.
Chiara B E MarleyDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA.
Carissa M FelicianoDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA.
Hannah L WatryGladstone Institutes, San Francisco, CA 94158, USA.
Quinn T CowanGladstone Institutes, San Francisco, CA 94158, USA.
Dylan SteuryGladstone Institutes, San Francisco, CA 94158, USA; University of California, Berkeley, Berkeley, CA 94720, USA.
Abin AbrahamVanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA; Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Erin N GilbertsonBiomedical Informatics Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA.
Grace D RameyBiomedical Informatics Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
John A CapraBakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Bruce R ConklinGladstone Institutes, San Francisco, CA 94158, USA; Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA. Electronic address: bconklin@gladstone.ucsf.edu.
Luke M JudgeDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA. Electronic address: luke.judge@ucsf.edu.

Funding

MEDICAL SCIENTIST TRAINING PROGRAMT32GM007347 · NIGMS · VANDERBILT UNIVERSITY · PI WILLIAMS, CHRISTOPHER S. · 1985 to 2023
$26.3M
The Evolution of Gene Regulation and Human DiseaseR35GM127087 · NIGMS · VANDERBILT UNIVERSITY · PI John Anthony Capra · 2018 to 2026
$3.2M
JAX-Gladstone, SCGE Disease Models Studies SupplementU01ES032673 · NIEHS · J. DAVID GLADSTONE INSTITUTES · PI CONKLIN, BRUCE R · 2020 to 2022
$2.4M
Allele-specific inactivation for dominant negative NEFL MutationsR01NS119678 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI JUDGE, LUKE M · 2021 to 2025
$1.9M
C9orf72 frontotemporal dementia (FTD) and amyotrophic lateral sclerosis(ALS): using patient cells and CRISPR to reveal therapeutic approachesR01AG072052 · NIA · J. DAVID GLADSTONE INSTITUTES · PI CONKLIN, BRUCE R · 2024 to 2025
$1.4M
Illumina NovaSeq 6000 Sequencing SystemS10OD028511 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHOW, ERIC D · 2020 to 2020
$583k
Investigating clinical risk between autoimmunity and Alzheimer’s Disease in diverse human populationsF31AG090013 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Grace Ramey · 2024 to 2026
$93k
NIA NIH HHS F31 AG090013NIA NIH HHS R01 AG072052NIEHS NIH HHS U01 ES032673NIGMS NIH HHS R35 GM127087NIGMS NIH HHS T32 GM007347NIH HHS S10 OD028511NINDS NIH HHS R01 NS119678
6 · The paper itself

Abstract

Inactivation of disease alleles by allele-specific editing is a promising approach to treat dominant-negative genetic disorders, provided the causative gene is haplosufficient. We previously edited a dominant NEFL missense mutation causing Charcot-Marie-Tooth type 2E (CMT2E) with inactivating frameshifts and rescued disease-relevant phenotypes in induced pluripotent stem cell (iPSC)-derived motor neurons. However, a multitude of different NEFL missense mutations cause CMT2E. Here, we addressed this challenge by targeting common single-nucleotide polymorphisms in cis with NEFL disease mutations for gene excision. We validated this haplotype editing approach in two iPSC lines with different missense mutations and demonstrated phenotypic rescue in iPSC-motor neurons. Surprisingly, our analysis revealed that gene inversion, a frequent by-product of excision editing, failed to reliably disrupt mutant allele expression. We deployed novel molecular assays to optimize our approach and achieve therapeutic levels of editing in immature iPSC-motor neurons. Finally, population genetics analysis demonstrated the power of haplotype editing to enable therapeutic development for the greatest number of patients. Our data serve as an important case study for many dominant genetic disorders amenable to this approach.

Indexed as

Charcot-Marie-Tooth DiseaseCRISPR-Cas SystemsGene EditingHaplotypesMutation, MissenseAllelesGenetic TherapyHumansInduced Pluripotent Stem CellsMotor NeuronsPhenotypePolymorphism, Single NucleotideCharcot-Marie-ToothCRISPRdominant-negativeexcisiongene editinginversioniPSCmotor neuronneurofilamentneuropathy

Identifiers

PMID41267399
PMCPMC12974165

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.