BackgroundInsomnia is highly prevalent among perimenopausal women and exerts detrimental effects on physical health, psychological well-being, and overall quality of life. However, its underlying mechanisms remain incompletely understood. This cross-sectional study aimed to identify factors associated with insomnia in perimenopausal women.MethodsA total of 187 perimenopausal women aged 45–55 years were enrolled. Insomnia, anxiety, and depression severity were assessed using the Insomnia Severity Index (ISI), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9), respectively. Serum levels of relevant amino acids and hormones were measured. Spearman correlation and linear regression analyses were performed to examine the associations among prolactin levels, tryptophan levels, insomnia, anxiety, and depression. Moderation analysis was further conducted to evaluate the potential moderating role of tryptophan in these relationships.ResultsSerum prolactin levels were positively associated with scores of ISI, GAD-7, and PHQ-9. Furthermore, prolactin levels were positively correlated with the severity of sleep-onset difficulties, sleep maintenance problems, noticeability of impairment, and sleep-related distress. Of note, serum tryptophan levels significantly moderated the association between prolactin levels and ISI scores (β = 0.227, 95% CI = 0.04–0.41, p = 0.0148). To wit, he positive relationship between prolactin levels and insomnia severity was stronger in perimenopausal women with higher serum tryptophan levels compared with those with lower levels.ConclusionsThe moderating effect of serum tryptophan on the relationship between prolactin levels and insomnia in perimenopausal women helps us understand the neuroendocrine mechanisms underlying perimenopausal insomnia and may inform future research on targeted preventive and therapeutic strategies.
Research trends and knowledge mapping of transcranial direct current stimulation in depression: a bibliometric study based on web of science, Scopus, and PubMed (2000-2025)
BackgroundDepressive disorders are clinically heterogeneous and mechanistically complex psychiatric conditions. Transcranial direct current stimulation (tDCS), a key non-invasive neuromodulation technique, has expanded rapidly in both therapeutic application and mechanistic research. However, the field is marked by rapid publication growth, thematic diversity, and variability in evidence quality. A systematic quantitative synthesis is therefore needed to map the research landscape, identify hotspots, and inform future directions.MethodsA systematic search was conducted for English-language publications in the Web of Science Core Collection (WoSCC), Scopus, and PubMed using the terms (“Transcranial direct current stimulation” OR “tDCS”) AND (“depression” OR “major depressive disorder” OR “depressive disorder” OR “MDD”). Only articles and reviews were included. Records from 2026 and non-research publications, including conference abstracts, editorials, letters, news items, and errata, were excluded. Deduplication was performed using DOI-based matching followed by title-assisted matching. Bibliometrix (R), VOSviewer, and CiteSpace were used to analyze publication trends, contributions by countries/regions, institutions, authors, and journals, collaboration networks, keyword co-occurrence, thematic clustering, and burst terms. Citation analysis was based on WoSCC data only.ResultsResearch on tDCS for depression showed sustained growth, with marked acceleration after 2020 and a peak in 2024. The United States, Germany, and Brazil occupied central positions in both productivity and international collaboration, with the United States ranking first in publication volume. Major research hubs included the Universidade de São Paulo, the University of Toronto, and Harvard University, while Brain Stimulation, Journal of Affective Disorders, and Frontiers in Psychiatry were the leading publication venues. Highly cited studies mainly focused on neurophysiological mechanisms, pivotal randomized controlled trials, and evidence-based guidelines. Keyword analyses indicated a shift from early attention to cortical excitability, safety, and short-term efficacy toward a more integrated framework involving prefrontal-targeted stimulation, cognitive function, functional connectivity, treatment outcomes, and cross-disorder applications.ConclusiontDCS research in depression is entering a multidimensional and interdisciplinary phase, with increasing emphasis on network-level mechanisms and precision intervention. Functional connectivity is emerging as a potential biomarker for patient stratification and outcome prediction. Further progress depends on multicenter standardization, reproducible analytic pipelines, and high-quality comparative effectiveness research.
Case Report: Prism for PTSD in severe traumatic brain injury with psychiatric comorbidities: two cases
BackgroundTraumatic brain injury (TBI) with post-traumatic stress disorder (PTSD) is treatment-resistant, with conventional psychotherapy showing limited efficacy due to neurocognitive impairments.Case SummaryWe report two patients with severe TBI and psychiatric comorbidities treated with Prism neurofeedback.Case 144-year-old female, 35 years post-childhood TBI, with agoraphobia and hyperacusis, achieved 42% PTSD reduction and substantial functional gains (social reintegration, independent driving) sustained through 4-month follow-up.Case 240-year-old male, 3.5 years post-adult TBI with bipolar II disorder and severe PTSD (PCL-5 = 62), achieved 90% PTSD reduction with complete remission sustained at 1-month follow-up, enabling return to work and family system transformation. Both patients developed personalized regulatory strategies and maintained gains without relapse.ConclusionsPrism neurofeedback demonstrates clinically meaningful outcomes in severe TBI-PTSD where traditional psychotherapy shows limited efficacy. The intervention’s circumvention of cognitive processing demands may explain the favorable outcomes. Controlled trials are warranted.
TxPert: using multiple knowledge graphs for prediction of transcriptomic perturbation effects
Nature Biotechnology, Published online: 01 May 2026; doi:10.1038/s41587-026-03113-4
TxPert predicts unseen single transcriptomic perturbations with accuracy approaching split-half experimental reproducibility.
DNA-guided CRISPR–Cas12a effectors for programmable RNA recognition and cleavage
Nature Biotechnology, Published online: 01 May 2026; doi:10.1038/s41587-026-03120-5
Synthetic DNA guides (crDNA) reprogram Cas12a nucleases for RNA targeting.
Rethinking triage for febrile children in low-resource settings
Nature Medicine, Published online: 01 May 2026; doi:10.1038/s41591-026-04387-6
Integrating clinical data with simple physiological measures or biomarkers improves triage of febrile children and could reshape frontline care in resource-limited settings.
Brazilian elimination of mother-to-child HIV transmission: lessons for large-scale global health systems
Nature Medicine, Published online: 01 May 2026; doi:10.1038/s41591-026-04373-y
Brazilian elimination of mother-to-child HIV transmission: lessons for large-scale global health systems
A communication subspace relays context-dependent actions from human prefrontal to motor cortex
Nature Neuroscience, Published online: 01 May 2026; doi:10.1038/s41593-026-02290-4
Context-dependent behavior selects actions according to task demands. Using direct brain recordings in humans, Binish et al. uncover how coordinated population activity efficiently channels information from prefrontal to motor cortex.
Approaches to Reducing Toxicity and Side Effects in Cell and Gene Therapy
Cell and gene therapy encompasses a broad range of therapeutic interventions for diseases that have proved refractory to treatment with conventional pharmaceutical approaches. Perhaps the most familiar FDA-approved modality in the cell and gene therapy field is chimeric antigen receptor (CAR) T-cell therapy, which involves genetic modification of a patient’s own T cells to identify and eliminate malignant cell lineages in acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma.
Although only 20 or so cell or gene therapies have been FDA-approved, the area holds considerable promise for investment. The global market was valued at nearly $9 billion in 2025, and growth has been projected at over 15% per year from 2026 to 2035. As with any pharmaceutical product, however, the potential of cell and gene therapy relies in large part upon minimizing risks to patient health from adverse effects. Numerous companies, from both prominent names in the field to smaller startups, are developing solutions to mitigate the deleterious consequences of cell and gene therapy.
Reducing cytokine release syndrome
Cytokines are a broad family of small proteins and peptides that cell lineages of the innate and adaptive immune systems employ to communicate with each other and coordinate timely and appropriately scaled responses to foreign antigen-containing cells. Cytokine release syndrome (CRS) occurs when hyperactivation of one or more immune lineages results in the release of excessive quantities of cytokines into the circulation.
“As a scientific community, we’ve been researching CAR T-cell therapy for over 30 years and have grown together in our understanding of the body’s immune response to treatment, from both a safety and efficacy perspective,” says Rosanna Ricafort, MD, vice president and global program lead of hematology and cell therapy at Bristol Myers Squibb. “We have evolved our ability to characterize, stage, and manage potential side effects, allowing for timely and thoughtful interventions of the most commonly associated side effects like CRS.”
Ricafort cited clinical data presented at the 2025 American Society for Clinical Oncology (ASCO) meeting in Chicago demonstrating that over 95% of instances of CRS and other adverse events arising from BMS’s CD19-directed CAR T-cell therapy (BreyanziR) occurred in the first two weeks after onset of therapy. “These and other studies have helped establish the largely predictable safety profile of CAR T-cell therapy to date,” Ricafort pointed out.
Minimizing side effects
The NF-κB and prostaglandin E2 pathways are prominent regulators of the activation and differentiation of pro-inflammatory T cell lineages. Excessive signaling through these pathways results in cytokine amplification, which contributes to CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), a complication of some types of CAR T-cell therapy.
CytoAgents, a clinical-stage biotech company, is developing CTO1681, an orally administered prostaglandin signaling inhibitor that has been shown to offset CRS and ICANS toxicities associated with CAR T-cell therapy of lymphoma patients. At the 2025 European Society for Medical Oncology (ESMO) Immuno-Oncology Congress in London, CytoAgents presented non-clinical data showing that CTO1681 treatment reduced secretion of TNF-α, IL6, and other key CRS-associated cytokines with no impairment of CAR T-cell mediated cytotoxicity on lymphoma cells.
“These data suggest CTO1681 could enable safer CAR T-cell therapy administration, support outpatient treatment paradigms, and broaden patient access without compromising anti-tumor efficacy,” said Teresa Whalen, CEO at CytoAgents. CTO1681 is currently in Phase Ib/IIa trials for cancer patients undergoing CAR T-cell therapy, with potential expansion into additional therapeutic spaces including asthma and chronic obstructive pulmonary disease.
Adding immunosuppressants
A potential side effect of adeno-associated virus (AAV)-based gene transfer approaches is acute liver injury resulting in part from CRS in patients receiving AAV therapy. Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder caused by mutations or changes in the DMD gene, resulting in reduced levels of the protein dystrophin.
Elevidys, developed by Sarepta Therapeutics, is an AAV-based therapy approved for the treatment of DMD that stimulates targeted production of a truncated form of dystrophin in skeletal muscle. “Individuals with non-ambulatory Duchenne face profound unmet need and fewer treatment options,” says Louise Rodino-Klapac, PhD, president of R&D and development and technical operations at Sarepta. Topline data released earlier this year showed that Elevidys treatment resulted in significant improvement in key clinical ambulatory metrics in patients.
As part of its ENDEAVOR clinical trial, Sarepta Therapeutics is evaluating the potential of supplementing Elevidys with sirolimus to reduce potential acute liver injury (ALI) complications. Sirolimus is a mammalian target of rapamycin (mTOR) kinase inhibitor that suppresses responses of T and B cells to interleukin 2, which functions to stimulate proliferation of helper, cytotoxic, and regulatory T cells.
Developing non-integrating therapies
As an alternative approach to supplementing cell and gene therapy modalities with existing immunosuppressants, other companies are modifying CAR T-cell therapy to reduce the risk of CRS and other side effects. Myasthenia gravis, a chronic fatigue-inducing autoimmune disorder in which signals between nerves and muscles are compromised, results in part from the secretion of autoantibodies from B-cell maturation antigen (BCMA)-expressing B plasma cells.
Conventional BCMA-directed CAR T-cell approaches rely on the integration of lentiviral or gamma-retroviral vectors to encode the CAR and typically involve lymphodepletion chemotherapy that can be accompanied by acute and delayed toxicity. In contrast, non-integrating (i.e., mRNA-based) BCMA-directed CAR T-cell therapies may circumvent this toxicity due to the lack of requirement for chemotherapy.
Cartesian Therapeutics is developing an mRNA-based BCMA-targeted CAR T-cell therapy for myasthenia gravis, Descartes-08. At the 2025 American Academy of Neurology (AAN) Annual Meeting in San Diego, results were reported of a Phase IIb clinical trial of Descartes-08 in myasthenia gravis. In the trial, adverse event rates were similar between groups receiving Descartes-08 and the placebo group, and were predominantly mild to moderate in nature, with no cases of CRS or ICANS reported.
“The impressive strength and duration of response shown in the data reinforce our confidence in the potential of Descartes-08 to transform the current treatment landscape in MG, offering patients a safe, flexible, and durable treatment option,” said Carsten Brunn, PhD, president and CEO of Cartesian.
Engineering chimeric receptors
Modifications of CAR T-cell therapy to improve clinical efficacy and reduce side effects can also encompass modification of the molecular structure of the chimeric receptor itself. D domains are highly selective targeting domains incorporated into newer generations of CARs that enhance targeting of pathological cell types and reduce immunogenic responses in patients that give rise to unwanted side effects.
One example of such next-generation CAR T-cell therapies, anito-cell, has been co-developed by Arcellx, Kite Pharma, and Gilead. Anito-cel is an autologous anti-BCMA CAR T-cell therapy for the treatment of relapsed/refractory multiple myeloma patients.
Phase II trial results in multiple myeloma presented at the 2025 American Society of Hematology (ASH) meeting in Orlando showed an overall response rate of 97% and a complete response rate of 68%. Importantly, in the context of side effects, there were no delayed neurological symptoms, and for most patients, only low-grade CRS was observed, which was resolved within a few days.
“The anito-cel D-domain BCMA binder could be important to our work in in vivo cell therapy, further strengthening our potential in oncology and inflammation,” said Daniel O’Day, chairman and CEO of Gilead. “Anito-cel could become a foundational treatment for multiple myeloma over time, including earlier lines of therapy.”
The post Approaches to Reducing Toxicity and Side Effects in Cell and Gene Therapy appeared first on GEN – Genetic Engineering and Biotechnology News.
Top 10 Best Selling Gene Therapies
The groundbreaking partnership that successfully treated a rare metabolic disorder in KJ Muldoon, or “Baby KJ,” with personalized CRISPR therapy last year has led therapy developers, researchers, and regulators, including the FDA, to craft a pathway for expanding the universe of gene therapies to advance the development of N-of-1 gene-editing therapies.
In February, the FDA unveiled its Plausible Mechanism Pathway draft guidance, a series of initiatives designed to increase regulatory flexibility and spur the development of bespoke gene-editing therapies for rare and ultra-rare disorders, which collectively total about 30 million individuals in the United States.
“The Agency anticipates that substantial evidence of effectiveness for individualized therapies could be established based on a single adequate and well-controlled clinical investigation with confirmatory evidence,” the draft guidance stated.
Last June, at a historic roundtable of cell and gene therapy researchers and clinicians hosted by the FDA, base editing pioneer David Liu, PhD, of Harvard University and the Broad Institute of MIT and Harvard, stated: “With sufficient organization and federal support and partnership with the FDA, I believe it will be possible by 2030 to treat at least 1,000 patients with personalized genetic treatments.”
Meanwhile, conventional gene therapy development continued in 2025. Last year saw four U.S. gene therapy approvals, bringing the number of FDA-approved gene and cell therapies up to 26, according to the American Society of Gene and Cell Therapies (ASGCT)—more than half of the 40 tallied by the organization as being approved worldwide.
Of those 26, 18 were gene therapies, of which 10 had disclosed sales high enough to be included on this A-List, which ranks top-selling gene therapies based on sales and net product revenue figures furnished by the companies in regulatory filings, annual reports, and/or press releases. Each gene therapy is listed with its sponsor(s), type, indication, and initial FDA approval date.
Not included are gene therapies with sales below the top 10, a category that includes two gene therapies approved in 2025: Precigen’s Papzimeos
(zopapogene imadenovec-drba), which generated $3.4 million in net product revenue last year after becoming the first-and-only FDA-approved treatment for adults with recurrent respiratory papillomatosis (RRP) in August; and Abeona Therapeutics’ Zevaskyn® (prademagene zamikeracel), an autologous cell sheet-based gene therapy approved to treat wounds in adults and children with recessive dystrophic epidermolysis bullosa (RDEB).
Three gene therapies did not have disclosed sales in 2025, including:
- Encelto (revakinagene taroretcel-lwey), an allogeneic encapsulated cell-based gene therapy marketed by Neurotech Pharmaceuticals and indicated for the treatment of adults with idiopathic macular telangiectasia type 2 (MacTel).
- Imlygic® (talimogene laherparepvec), a genetically modified oncolytic viral therapy marketed by BioVex (Amgen) and indicated for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.
- Waskyra (etuvetidigene autotemcel), a cell-based gene therapy and the first FDA-approved treatment for Wiskott-Aldrich syndrome (WAS). Developer Fondazione Telethon is the first non-profit organization to have successfully led full development of an ex vivo gene therapy from lab research (at Milan’s San Raffaele Telethon Institute for Gene Therapy or SR-Tiget) to regulatory approval.
Also not included this year are sales of three gene therapies that had been marketed by Bluebird Bio: Beta thalassemia treatment Zynteglo (betibeglogene autotemcel), sickle cell disease treatment Lyfgenia® (lovotibeglogene autotemcel), and cerebral adrenoleukodystrophy (CALD) treatment Skysona® (elivaldogene autotemcel).
Last year, Bluebird Bio went private after being acquired by funds managed by Carlyle and SK Capital Partners, then rebranded in September as Genetix Biotherapeutics. Genetix does not disclose sales but did announce on March 2 that more than 100 patients received infusions of the three gene therapies during 2025.
Also last year, Pfizer halted development and commercialization of Beqvez (fidanacogene elaparvovec-dzkt), which had been co-marketed with Roche-owned Spark Therapeutics, after it generated no sales in 2024. Last August, Pfizer terminated its license agreement with Spark for Beqvez, an adeno-associated virus (AAV) vector-based gene therapy indicated for forms of moderate to severe hemophilia B in adults.
Top 10 Best Selling Gene Therapies |
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1. Zolgensma® (onasemnogene abeparvovec-xioi) 2025 Sales: $1.232 billion 1 Sponsor(s): Novartis2 Type: AAV vector-based gene therapy Indication(s): Treatment of pediatric patients less than two years of age with spinal muscular atrophy (SMA) with biallelic mutations in the survival motor neuron 1 (SMN1) gene. Initial FDA Approval Date: May 24, 2019 |
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2. Elevidys® (delandistrogene moxeparvovec-rokl) 2025 Sales: $898.7 million Sponsor(s): Sarepta Therapeutics Type: AAV vector-based gene therapy Indication(s): Treatment of ambulatory pediatric patients aged four through five years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.3 Initial FDA Approval Date: June 22, 2023 (Accelerated Approval) |
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3. Vyjuvek® (beremagene geperpavec-svdt) 2025 Sales: $389.13 million Sponsor(s): Krystal Biotech Type: Herpes-simplex virus type 1 (HSV-1) vector-based gene therapy Indication(s): Treatment of wounds in patients six months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene. Initial FDA Approval Date: May 19, 2023 |
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4. Adstiladrin® (nadofaragene firadenovec-vncg) 2025 Sales: €172.673 million ($199.329 million) Sponsor(s): Ferring Pharmaceuticals Type: Non-replicating adenoviral vector-based gene therapy Indication(s): Treatment of adults with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. Initial FDA Approval Date: December 16, 2022 |
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5. Casgevy® (exagamglogene autotemcel; “exa-cel”) 2025 Sales: $115.8 million Sponsor(s): Vertex Pharmaceuticals and CRISPR Therapeutics Type: Autologous genome-edited hematopoietic stem cell-based gene therapy Indication(s): Treatment of patients aged 12 years and older with sickle cell disease with recurrent vaso-occlusive crises (VOCs), or transfusion-dependent β-thalassemia (TDT). Initial FDA Approval Date: December 8, 2023 |
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6. Hemgenix® (etranacogene dezaparvovec-drlb) 2025 Sales: A$92 million ($64.9 million)4 Sponsor(s): CSL Behring Type: AAV vector-based gene therapy Indication(s): Treatment of adults with Hemophilia B (congenital Factor IX deficiency) who currently use Factor IX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes. Initial FDA Approval Date: November 22, 2022 |
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7. Kebilidi 2025 Sales: $56.626 million Sponsor(s): PTC Therapeutics Type: AAV vector-based gene therapy Indication(s): Treatment of adult and pediatric patients with aromatic L-amino acid decarboxylase (AADC) deficiency. Initial FDA Approval Date: November 13, 2024 |
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8. Luxturna® (voretigene neparvovec-rzyl) 2025 Sales: CHF 41 million ($51.8 million) Sponsor(s): Spark Therapeutics (Roche) Type: Adeno-associated virus vector-based gene therapy Indication(s): Treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Patients must have viable retinal cells as determined by the treating physician(s). Initial FDA Approval Date: December 18, 2017 |
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9. Lenmeldy 2025 Sales: ¥6.4 billion ($40.2 million) Sponsor(s): Orchard Therapeutics (a wholly owned subsidiary of Kyowa Kirin) Type: Autologous hematopoietic stem cell-based gene therapy Indication(s): Treatment for children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ), or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD). Initial FDA Approval Date: March 18, 2024 |
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10. Roctavian® (valoctocogene roxaparvovec-rvox; “val-rox”) 2025 Sales: $36 million Sponsor(s): BioMarin Pharmaceutical Type: AAV vector-based gene therapy Indication(s): Treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without pre-existing antibodies to AAV serotype 5 detected by an FDA-approved test. Initial FDA Approval Date: June 30, 2023 |
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