Tag: Genomics

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D&D‑seq Uses Base Editing to Map DNA–Protein Interactions in Single Cells

A new molecular recording strategy is giving researchers a way to capture DNA–protein interactions in single cells, including the weak and transient contacts that shape gene regulation but often slip past existing assays. The method, called D&D‑seq (docking and deamination followed by sequencing), layers a base‑editing enzyme onto an antibody‑binding nanobody, turning fleeting interactions into durable sequence marks.

The paper is titled “Single-cell mapping of regulatory DNA-protein interactions,” and was published recently in Cell.

“D&D-seq couples an antibody-binding nanobody to a cytosine base editor, a combination that enables detection of weak or transient factor binding through targeted cytosine-to-uracil [C→U] editing at protein-bound genomic sites,” the authors wrote. Those edits become a molecular breadcrumb trail, revealing where regulatory proteins have interacted with the genome.

This approach directly addresses a long‑standing gap in the field. Traditional methods for mapping transcription factor binding, such as ChIP‑seq or CUT&RUN, “cannot be easily incorporated into high-throughput single-cell workflows, limiting applications to bulk analysis or to single-cell profiling of only the strongest interacting chromatin factors. Single-cell profiling of TF binding in primary samples has been mainly restricted to inferential approaches based on expression levels of downstream TF target genes or through motif analysis of assay for transposase-accessible chromatin using sequencing (ATAC-seq) peaks, but identification of specific TF-binding sites requires more direct methods,” according to the authors.

The team demonstrated that D&D‑seq can map binding sites for transcription factors and other regulatory proteins, like chromatin remodeling proteins, across multiple cell types and conditions. One application involved profiling CTCF binding in primary T cells carrying an IDH2 mutation commonly found in leukemia. Because D&D‑seq operates at single‑cell resolution, it exposes heterogeneity in regulatory wiring that is often masked in population‑level assays.

Crucially, the method is platform‑agnostic. The authors showed that D&D‑seq can be integrated into standard single‑cell multiomics workflows, including ATAC‑seq, scATAC‑seq, and whole‑genome sequencing. That compatibility allows researchers to pair DNA–protein interaction maps with chromatin accessibility, gene expression, and genomic variation—all within the same cell.

As transcription factors and other regulatory proteins increasingly emerge as therapeutic targets, tools that reveal how these factors behave in patient‑derived cells will be essential. D&D‑seq offers a way to monitor how mutations, drugs, or engineered perturbations reshape regulatory landscapes at single‑cell resolution.

“We’re entering an era of medicine in which transcription factors and other gene-activity regulators will increasingly be therapeutic targets,” said Dan Landau, MD, PhD, the Bibliowicz Family professor of medicine and a member of the Sandra and Edward Meyer Cancer Center and the Englander Institute for Precision Medicine at Weill Cornell, who is also an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. “This kind of technology should have an important role in developing and evaluating such therapies.”

Although the method is still evolving, its conceptual elegance and technical flexibility have already sparked broad interest. By turning DNA into a recording surface for protein activity, D&D‑seq opens a new window into the “regulome”—one that captures the subtle, transient interactions that drive cellular identity and disease.

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Alzheimer’s Genetic Risk Loci: 16 New Candidates

A comprehensive international genetics study found several new genetic risk factors for Alzheimer’s disease and related dementias, providing one of the clearest pictures of the biological pathways that cause the devastating neurodegenerative disorder.

Published in the journal Nature Genetics, the study combined data from 978,514 people of European ancestry, including over 128,681 individuals with Alzheimer’s disease and related dementias (ADRD). The researchers found 91 regions of the genome linked to dementia risk, including 16 new loci that had not been linked to Alzheimer’s in European populations.

The project brought together several major research consortia, including the European Alzheimer and Dementia Biobank, the International Genomics of Alzheimer’s Project, and the Psychiatric Genomics Consortium. By pooling results from 52 studies, scientists created one of the largest and most comprehensive genome-wide association analyses ever conducted for Alzheimer’s research.

Although aging is the strongest risk factor for Alzheimer’s disease, which affects tens of millions of people worldwide, genetics plays a major role in disease development. The APOE ε4 gene is known to strongly increase Alzheimer’s risk, but scientists believe many additional genes contribute smaller effects that together shape vulnerability.

The new study significantly expands that genetic map. Newly identified risk regions include genes involved in immune signaling, lipid metabolism, and cellular waste disposal—processes already suspected to contribute to the buildup of amyloid plaques and tau tangles, the hallmark pathologies of Alzheimer’s disease.

Several of the newly discovered loci, including SRC, PTPRC, MGAT5, and DOCK4, point toward the importance of microglia, the brain’s immune cells. Previous studies have suggested that dysfunctional immune responses may accelerate neurodegeneration by impairing the brain’s ability to clear toxic proteins.

Researchers also found evidence that many Alzheimer’s-associated genes are highly active in microglia across multiple brain regions, reinforcing the idea that inflammation and immune regulation are central to disease progression.

To distinguish true Alzheimer’s signals from broader dementia-related effects, the team performed additional analyses excluding “proxy” cases—individuals reporting a parent or sibling with dementia—and excluding large biobank datasets based primarily on medical coding. Even under these stricter conditions, 56 of the identified loci remained strongly associated with clinically diagnosed Alzheimer’s disease, suggesting the findings are robust.

Beyond identifying genes, the researchers tested how combined genetic risk influences brain pathology. They created polygenic risk scores using Alzheimer’s-associated variants other than APOE and examined their relationship to postmortem brain changes.

Individuals in the highest 10% of genetic risk had roughly double the likelihood of severe tau tangles and amyloid plaque buildup compared with people in the middle-risk group. Conversely, individuals in the lowest 10% had substantially reduced risk.

Importantly, the genetic scores were more strongly linked to classic Alzheimer’s pathology than to other forms of brain damage such as strokes or vascular disease. This suggests that many of the identified variants specifically contribute to Alzheimer’s biological mechanisms rather than dementia in general.

Despite the scale of the study, researchers caution that genetics alone cannot fully predict who will develop Alzheimer’s. The polygenic scores explained only a modest portion of disease variability, highlighting the continued importance of environmental and lifestyle factors.

Still, scientists say the findings could help accelerate the search for new drug targets and improve future risk prediction tools. The study also emphasizes the necessity of larger and more diverse datasets, as the current analysis focused primarily on individuals of European ancestry.

Future work will examine how rare genetic variants and structural changes in DNA contribute to Alzheimer’s biology, potentially paving the way to precision medicine and earlier intervention.

 

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Genetically Raised Pulse Pressure Predisposes to Dementia-Linked Death

People who carry a higher number of genetic variants for increased pulse pressure may be at increased risk of having dementia as a contributing factor in their deaths, research suggests.

The findings, in Neurology, point to shared genetics underpinning cardiometabolic disease and dementia.

Although it is known that cardiometabolic conditions such as high blood pressure, diabetes, and stroke are associated with the neurodegenerative disease, it has been unclear how genetic predictors for the former influence the latter.

Pulse pressure is the difference between systolic and diastolic pressure and a higher number is indicative of poorer cardiac health, such as hardened arteries or poor heart function.

“While having the APOE ɛ4 allele, a gene variant, is the strongest common genetic risk factor for Alzheimer’s disease, some people may inherit a combination of small effect gene variants linked to cardiometabolic disease that may also increase the risk,” explained researcher Laura Raffield, PhD, from the University of North Carolina at Chapel Hill.

“Our study found an association with genetic variants linked to high pulse pressure and an increased risk of death from dementia.”

Late-life dementia is strongly inherited, with genetics responsible for around 60% to 80% of Alzheimer’s disease.

While the APOE ɛ4 allele is a well-known genetic risk factor for Alzheimer’s disease, other common genetic variants have been implicated and there may also be vascular contributions.

The study investigated how polygenic risk scores for cardiometabolic disease related to dementia-related outcomes among more than 8000 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.

The authors note that REGARDS has particularly high numbers of Black participants, who are underrepresented in late-life dementia research, and eight in 10 in the current study identified as non-Hispanic Black.

Study participants had a mean age of 63.7 years at the start of the study and underwent screening for cognitive function annually. They were followed for up to 14 years for risk of death from dementia and nine years for cognitive impairment, on average.

A total of 619 people developed cognitive impairment during this time compared with 7159 with no such impairment. The 459 individuals who had dementia listed as a cause of death were compared with 8362 who died from other causes or for whom the reason was missing.

A higher polygenic risk score for pulse pressure was associated with a 16% increased risk of dementia as a contributing cause of death, after accounting for potential confounding factors.

This statistically significant result was not seen in polygenic risk scores for systolic or diastolic blood pressure, potentially supporting earlier research indicating that pulse pressure is a better predictor of coronary heart disease.

The polygenic risk score for pulse pressure was not associated with incident cognitive impairment, suggesting limited shared genetics between this dementia-related outcomes.

Overall, there were significant or nominal associations in polygenic risk scores for triglycerides, pulse pressure, type 2 diabetes and both the endpoint of Alzheimer’s disease and related dementias and also dementia as a contributing cause of death. However, this was not the case with incident cognitive impairment.

In addition, the results confirmed that the APOE variant was a predictor of both dementia as a contributing cause of death and incident cognitive impairment, and that local African ancestry was associated with nominally attenuated effect size.

The authors concluded that the inconsistent results between incident cognitive impairment and dementia as a contributing cause of death “imply that different dementia-related end points may capture distinct biological pathways.”

They elaborated: “For example, genetic risk factors of [cardiometabolic diseases] may be more strongly related to later disease progression, such as amyloid accumulation throughout later life, rather than to early cognitive impairment.”

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New Tumor Survival Mechanism Revealed in Aggressive ALT Cancers

Researchers at the University of Pittsburgh have uncovered an unexpected relationship between two of the genome’s most distinct chromosomal structures, revealing how aggressive cancers that rely on the alternative lengthening of telomeres (ALT) pathway may adapt to sustain their growth.

The study, published in Nature, shows that centromeric DNA sequences and chromatin components become incorporated into telomeres in ALT-positive cancers, creating a previously unrecognized genomic signature that appears to help maintain telomere integrity. The findings provide new insight into how cancers driven by ALT evolve and may ultimately reveal vulnerabilities that could be therapeutically exploited.

“Telomeres and centromeres are not known to interact,” said senior author Roderick O’Sullivan, PhD, professor of pharmacology and chemical biology at the University of Pittsburgh and UPMC Hillman Cancer Center. “They’re not known to occupy the same regions of the genome. This is a really bizarre and unique event that is being captured in this specifically pathogenic context.”

ALT, or alternative lengthening of telomeres, is a specialized telomere maintenance mechanism used by approximately 5% to 10% of cancers. Unlike most tumors, which reactivate telomerase to extend telomeres and achieve replicative immortality, ALT-positive tumors rely on recombination-based mechanisms to lengthen chromosome ends. ALT is particularly enriched in aggressive subsets of sarcomas, gliomas, pancreatic neuroendocrine tumors, and other mesenchymal-derived cancers.

Although ALT has long been associated with genome instability and epigenetic dysregulation, researchers had not previously identified specific genomic rearrangements generated during ALT activation.

In the new study, O’Sullivan and colleagues discovered that centromeric DNA repeats become inserted into telomeric regions specifically in ALT cancer cell lines and primary pediatric neuroblastoma samples. The findings challenge a long-standing assumption that telomeres and centromeres remain physically and functionally separated within the nucleus.

“Centromeres and telomeres typically occupy exclusive nuclear territories,” said co-corresponding author Yael Nechemia-Arbely, PhD. “When we first saw the results, I was very skeptical. It took a long time and a lot of quantification and looking at it from many different angles to convince us that this was real.”

The investigators traced the phenomenon to loss of ATRX, a chromatin-remodeling protein frequently mutated in ALT-positive cancers and widely used as a biomarker of ALT status. Loss of ATRX has long been linked to telomere dysfunction, but the new work suggests it may simultaneously destabilize centromeric regions, creating conditions that enable interactions between two chromosomal domains that are normally kept apart.

“What we think is going on is that when ATRX is gone, you’ve not only destabilized telomeres, but you’ve also destabilized centromeres,” O’Sullivan said. “Now you have these two exposed domains that either through chance or necessity are interacting, and the ultimate byproduct of that transaction is the insertion of DNA repeats from the centromere into the telomere.”

The researchers found that epigenetic dysregulation caused by ATRX loss, together with DNA hypomethylation, promoted acquisition of these centromeric chromatin signatures at telomeres.

Ragini Bhargava, PhD, co-corresponding author of the study, said the findings expand current understanding of how ALT-associated telomeres evolve. “For a long time, the field viewed ALT as telomeres recombining with other telomeres,” Bhargava said. “What this study is showing is that when you lose ATRX, telomeres become prone not only to recombination within telomeres but also with other parts of the genome. One of those regions is the centromere, which should be highly protected and spatially very far away from telomeres.”

The team also demonstrated that the centromeric material incorporated into telomeres is not merely a passive byproduct of genome instability. Functional experiments showed that disrupting HJURP-mediated deposition of CENP-A compromised telomere integrity, impaired ALT activity, and triggered aberrant telomeric mitotic DNA synthesis. Those results suggest that centromeric chromatin becomes functionally integrated into the telomere maintenance machinery of ALT cancers.

“What’s interesting is that the DNA repeats from the centromere are actually doing something,” O’Sullivan said. “They’re bringing machinery to the telomere, and somehow the telomere is adapting and using that to protect itself so that the cancer cell can keep growing.”

The work points to a previously unrecognized form of interchromosomal communication that may help explain how ALT-positive tumors survive despite extensive genomic instability.

Clinically, the findings are not yet ready to translate into a therapeutic strategy, the authors cautioned. However, they may eventually provide new biomarkers or reveal dependencies unique to ALT-driven tumors.

“We have a documentation of something within the series of events that happens as these cells become highly detrimental,” O’Sullivan said. “This is a new signature of that process.”

Because proteins involved in centromere function are essential for normal cellular processes, directly targeting the newly identified pathway may prove challenging. Nevertheless, the researchers believe the discovery opens a new area of investigation into ALT biology.

“In my view, this is the beginning,” O’Sullivan said. “There could be other machinery that these centromere proteins are bringing that will provide a vulnerability that could be targeted.”

The findings suggest that aggressive ALT-positive cancers have evolved an unexpected strategy for preserving chromosome ends, co-opting centromeric DNA and chromatin to reinforce telomere function. In doing so, they reveal a previously hidden connection between two of the genome’s most fundamental structures and provide new insight into how cancer cells sustain limitless growth.

 

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Veracyte Launches Test Identifying Breast Cancer Patients Who Don’t Need Chemo

Buoyed by the remarkable results of the OPTIMA trial presented at the ASCO Annual Meeting, Veracyte this week announced the U.S. launch of the Prosigna Breast Risk of Recurrence (ROR) test, a genomic test for patients diagnosed with early-stage hormone-receptor positive (HR+) breast cancer. 

“Prosigna is the only test proven to be predictive for chemotherapy benefit in a Phase III prospective trial for patients with up to nine positive lymph nodes, including premenopausal women, all of whom were recommended to receive ovarian suppression,” Phillip G. Febbo, MD, chief scientific and medical officer at Veracyte, told Inside Precision Medicine. 

The Prosigna test determines a patient’s ROR score and estimates the 10-year probability of distant recurrence. It thus help guide treatment decisions, including predicting whether high risk patients are likely to benefit from chemotherapy or may safely achieve optimal outcomes with endocrine therapy alone, helping clinicians to make personalized care plans for their patients. 

Prosigna will be available to order starting June 8, 2026.

“Every patient diagnosed with breast cancer deserves answers they can trust about what their cancer means and what comes next,” said John Leite, PhD, chief commercial officer, Veracyte​.

“Prosigna gives patients and their oncologists a deeper understanding of their individual risk of recurrence, and, for many, whether chemotherapy will truly benefit them or whether they can safely avoid it. That kind of personalized insight can bring greater confidence and reassurance as patients navigate decisions that will shape their care and future health.”

In the U.S., more than 225,000 new HR+/HER2- breast cancer cases are diagnosed each year. When breast cancer is diagnosed early and treated appropriately, five-year survival rates reach 92%.

“For decades, clinical staging just comprised tumor size and nodal status together with pathology. This was the standard approach to determining whether patients with HR+/HER2- breast cancer need chemotherapy. Many node-positive patients routinely receive chemotherapy as standard of care,” Febbo said.

He added, “And yet, chemotherapy is likely to only benefit a relatively small fraction of these patients.” 

The OPTIMA trial uses the Prosigna test to guide therapy and testing. Those patients with a low Prosigna ROR (<60) can safely avoid chemotherapy. OPTIMA shows that tumor biology, as evaluated by the Prosigna test, provides information beyond traditional clinical factors.

Prosigna is based on the PAM50 genomic classifier, which classifies tumors into four intrinsic subtypes. Prosigna, the company said in a press release, “uniquely combines intrinsic subtypes and proliferation score with clinical pathological factors into a single comprehensive analysis to calculate a patient’s Risk of Recurrence (ROR) score and predict 10-year probability of distant recurrence.”  

Veracyte’s portfolio includes multiple cancer types, including tests for prostate cancer (Decipher Prostate), bladder cancer (Decipher Bladder and TrueMRD for muscle invasive bladder cancer monitoring), and others. The company said, “Prosigna’s intrinsic subtyping data positions us well for future expansion. While ROR scoring is specific to HR+/HER2- disease, the underlying intrinsic subtyping information spans all breast cancer types.” 

More than 225,000 new HR+/HER2- breast cancer cases are diagnosed annually, with approximately 75,000 patients having node-positive disease annually. The OPTIMA trial demonstrated that more than two-thirds of clinically high-risk patients (68%) can safely avoid chemotherapy—a significant population previously assumed to require treatment based solely on nodal status. 

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SMArT Platform Improves Safety and Efficiency of CRISPR Editing in HSPCs

Researchers at the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) in Italy have developed a gene editing platform they say improves the precision and safety of CRISPR-Cas9 gene editing in human hematopoietic stem and progenitor cells (HSPCs), a development that addresses the long-standing difficulty of ensuring that edited stem cells carry only the intended genetic change without unintended genomic alterations. Details of the new platform, called SMArT (Selection by Means of Artificial Transactivators), are published in Nature Biotechnology.

“These unintended outcomes, such as large deletions of DNA sequences, have emerged as one of the most important limitations to the broader application of gene editing, especially in stem cells intended for transplantation,” said senior author Luigi Naldini, MD, PhD, director of SR-Tiget. “With SMArT, we aimed to create an intelligent selection system capable of identifying and enriching only those cells that achieved the desired genetic correction while excluding cells carrying potentially dangerous alterations.”

CRISPR-based therapies such as exagamglogene autotemcel (Casgevy) have already reached regulatory approval for hemoglobinopathies, the vanguard of the expected wave of CRISPR-based gene therapies. But drugs like Casgevy use CRISPR to knock out the disease causing gene, while approaches aimed at creating homology-directed repair (HDR), whereby a gene is inserted have been plagued by unintended genetic changes at the editing site. To date, HDR has been constrained by cell cycle limitations and competing DNA repair pathways that can generate deletions, rearrangements, and other structural changes at the target location.

SMArT was developed to address both low HDR efficiency and the unintended heterogeneity of the gene editing approaches. To do this the investigators created a method whereby transient synthetic “AND-gate” circuits are activated only when two conditions are met: successful targeted integration of a gene-sized cassette and preservation of correct genomic architecture at the edited locus. Only these cells transiently express a selectable marker, enabling their enrichment while removing cells carrying aberrant edits.

“HDR-edited HSPCs were enriched to 80–100% purity through transient selector expression, whereas cells carrying undesired and potentially genotoxic on-target edits were preferentially depleted,” the researchers wrote. They also showed that after transplantation into immunodeficient mice, the enriched cells sustained long-term human hematopoiesis, and the selector system was no longer detectable.

SMArT was developed in three configurations SMArT-1, SMArT-2, and SMArT-3. The most advanced version, SMArT-3, employs a CRISPR-based regulatory architecture that can detect correct integration of the edit at the intended site while also transiently activating genes to support stem cell engraftment. One version of this system uses a single programmable CRISPR-based regulatory system to reduce the need for multiple components.

In preclinical models, SMArT was tested in human HSPCs targeting loci relevant to inherited immune disorders, including X-linked severe combined immunodeficiency (SCID-X1) and Hyper-IgM syndrome. The system successfully enriched for correctly edited cells while reducing large deletions and other structural abnormalities associated with CRISPR-induced DNA repair. The selected cells demonstrated multilineage differentiation capacity after engraftment in mice, exhibiting preserved stem cell function.

“Our goal was not simply to improve editing efficiency, but to fundamentally rethink how to control the quality of edited cell products,” said co-senior author Samuele Ferrari, PhD, a project leader at SR-Tiget. “SMArT introduces a programmable framework that can simultaneously increase precision, reduce genotoxic burden, and preserve the functional potential of stem cells.”

The researcher noted that the SMArT platform is designed to be usable across loci and compatible with other genome engineering technologies beyond CRISPR-Cas9, including emerging targeted integration systems. The also believe it can be used to address multiple genetic diseases, particularly those requiring durable correction of blood or immune cell lineages.

Next steps include improving manufacturing efficiency, preserving clonal diversity during selection, and optimizing delivery methods for HDR templates. SMArT will also need evaluation to determine how it performs across different disease contexts and stem cell sources, as well as how it may integrate with non-myeloablative conditioning approaches to therapeutic development.

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Illumina Announces MRD Kit Ahead of ASCO Meeting

Ahead of the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, kicking off this weekend, Illumina has announced a new molecular residual disease (MRD) product. The distributed kit enables solid tumor MRD and blood cancer genomic profiling and, the company says, will enable more labs to adopt MRD detection for clinical research.

It is the first in a new portfolio of WGS oncology research offerings, with additional solutions in development leveraging the latest advancements of the NovaSeq X. Illumina’s MRD research solution is available today for early access to select partners and will launch for global customers next year.

“In precision healthcare, early and accurate detection of molecular residual disease is critical to monitoring patients during and after cancer treatment,” said Todd Christian, senior vice president of Services, Arrays, and Genomic Access at Illumina. “Illumina’s MRD solution for clinical research leverages the advanced sensitivity of whole-genome sequencing, coupled with unparalleled analysis, to enable our customers to more easily deliver the most precise information to advance MRD research. We aim to make WGS in oncology more accessible and scalable to support the integration of precision solutions into the standard of care.”

The MRD solution supports fingerprinting through solid tumor samples, and MRD detection using blood samples, all compatible on NovaSeq Systems. The end-to-end research workflow can be completed in as fast as five days and is optimized for analytical sensitivity as low as 10 ppm, particularly important for early-stage and low-shedding tumors, including breast, ovarian, and renal.

Illumina’s DRAGEN MRD analysis connects each fingerprint to serial circulating tumor DNA (ctDNA). The new MRD solution has been optimized across thousands of samples to develop and demonstrate a ctDNA detection algorithm with 99.5% analytical specificity to distinguish true tumor signals from background noise.

Mayo Clinic evaluated the solution on a small sample cohort and found high concordance among previously characterized paired samples. The results were also highly correlated with clinical and imaging results over time. The team is planning to expand the cohort for additional research with Mayo Clinic and other academic partners.

“We are looking forward to participating in early access and evidence generation for a tumor-informed, non-bespoke whole-genome sequencing approach to MRD,” said Gang Zheng, MD, PhD and professor of Laboratory Medicine and Pathology at Mayo Clinic. “We have seen early pilot results across several solid tumor clinical samples that demonstrated the potential utility of highly sensitive solid tumor MRD detection, and we continue to pilot technologies that help us efficiently progress in our ability to analyze and translate complex genomic arrays.”

Built on recently announced NovaSeq X advancements, including 35B output and Q70 quality scores, a complementary research workflow that will deliver ultra-sensitive MRD detection in the single-digit ppm range leveraging duplex reads is currently in development.

Illumina’s new oncology portfolio builds upon the integrated ecosystem of workflows, data and community across genomic, multiomic, and clinical research applications—anchored on the NovaSeq X.

Illumina and Bristol Myers Squibb will jointly present a poster at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting on Sunday, May 31, from 9:00 a.m. to 12:00 p.m. (abstract ID 8591, poster board #381, Lung Cancer: Non–Small Cell Metastatic track).

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PRINCE: A Small-Molecule Switch for Safer Gene Editing

Although gene editing has enormous clinical promise, it still faces many obstacles that must be overcome before broad translation. For example, the genome editing field is continuously working to increase the safety of the technique. One way to do that is to control the duration of gene editing activity. However, achieving precise temporal control over these platforms is challenging.

Scientists currently lack tools that can precisely control the duration of gene editing therapies, to halt their effects after a few months or years. Researchers have developed several potential solutions, including degradable protein- or RNA-based systems, but existing approaches face limitations such as only being applicable in the liver.

Now, a new gene editing system, named PRINCE, with inducible nuclease proteins and guide RNAs, enables researchers to control the duration and specificity of gene therapies precisely with small molecules—potentially addressing a longstanding safety concern in the field.

This work is published in Science Translational Medicine in the paper, “Coordinated regulation using small-molecule drugs enables controlled therapeutic genome editing and enhanced genomic precision in situ.“

In the PRINCE CRISPR-Cas gene editing system, expression of the nuclease and the guide RNA is separately inducible by two approved small molecule drugs, enabling both temporal control and reduced off-target editing.

The platform was stable for as long as two years after genomic integration in cultured human cells. In addition, a smaller system, called Little Prince, showed promising signs of efficacy in humanized mouse models of elevated cholesterol levels and age-related macular degeneration. Little Prince uses compact nucleases that can be delivered in a single adeno-associated viral vector (AAV) for delivery.

In two mouse models, Little Prince reduced excessive cholesterol levels in mice with genetic hypercholesterolemia and showed signs of reducing lesion size in rodents with laser-induced choroidal neovascularization—a model of age-related macular degeneration.

More specifically, Little Prince “ameliorated pathological phenotypes of hypercholesterolemia (average reductions of 45% and 47% in serum total cholesterol and low-density lipoprotein cholesterol, respectively) and neovascular age-related macular degeneration, with significantly reduced lesion size and leakage (P < 0.0001).”

The system produced fewer off-target edits and lower off-target editing frequencies than constitutive nuclease expression, highlighting the utility of precise temporal control.

“PRINCE and Little Prince also provide […] capabilities that might also be useful for research objectives that include lineage tracing and conditional genetic engineering work,” the authors noted. These results, they asserted, position PRINCE and Little Prince as controlled genome editing platforms with potential for in vivo, particularly in situ, therapeutic applications.

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