Swiss Institute for Regenerative Medicine

Arthritis in K/BxN mice is provoked by pathogenic autoantibodies to glucose-6-phosphate isomerase (G6PI), which is a ubiquitously expressed enzyme that is present in cells, in the circulation and on articular cartilage. When G6PI autoantibodies (auto-Abs) deposit on the articular cartilage of K/BxN mice, arthritis ensues due to the activation of various components of the innate immune system. Recent studies have investigated the in vivo efficacy of recombinant fragment-crystallizable (Fc) protein-based therapeutics. Many recombinant Fc proteins evaluated provide protection against inflammation in mouse models of arthritis, such as the K/BxN serum-transfer model. More recently, rFc-µTP-L309C, a recombinant human IgG1-Fc with an additional point mutation at position L309C fused to the human IgM tailpiece to form a hexamer, has been shown to ameliorate the arthritis in K/BxN mice. Additional studies have shown that rFc-µTP-L309C has multiple effects that work together to ameliorate the arthritis, including inhibition of neutrophil migration into the joint, inhibition of IL-1β production, downregulation of Th1 and Th17 cells, and increases in T regulatory cells and synovial fluid IL-10. In this work, rFc-µTP-L309C was shown to effectively prevent arthritis in the K/BxN serum-transfer model, significantly downregulate inflammatory cytokines/chemokines, and ameliorate the arthritis in the endogenous K/BxN model. This amelioration of the arthritis was associated with a significant decrease in autoantibody levels, which was independent of the neonatal Fc receptor (FcRn). rFc-µTP-L309C was shown to specifically inhibit G6PI autoantibody secretion from B-cells with a concomitant increase in TGFβ and decrease in B-cell activating factor (BAFF). These new findings suggest that rFc-µTP-L309C may provide a therapeutic benefit for other antibody-mediated autoimmune diseases through its effects on B-cells.

Stroke is one of the leading causes of disability worldwide. Although preclinical studies have shown promising results of pharmacotherapies to enhance stroke recovery, no drug has been approved for stroke recovery in patients. In this article, we review the preclinical data of one promising treatment, inhibition of NgR1 (Nogo receptor 1) signaling, for stroke recovery. Our scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews and surveyed the peer-reviewed literature on PubMed and citation searching. Studies were eligible if they evaluated the pharmacological inhibition of Nogo/NgR1 signaling in nonhuman models of stroke assessing sensorimotor or functional outcomes. There were no restrictions in years considered. An assessment of the risk of bias was performed using the Systematic Review center for Laboratory Animal Experimentation tool. Three hundred seventeen articles were screened based on the inclusion criteria. Thirty preclinical studies were included. Most studies (90%) were conducted in rodents, with only 3 studies (10%) completed in nonhuman primates. Anti-Nogo-A antibody was the most common pharmacological intervention, used in 21 (70%) studies. Most preclinical studies delivered the study drug directly into the central nervous system (intrathecal, intraventricular, or intraparenchymal), with far fewer studies (n=5) testing subcutaneous, intravenous, or intranasal administration. Among the 30 studies included, 27 (90%) report a beneficial effect. In conclusion, there is a large body of preclinical evidence to support Nogo/NgR1 inhibition in promoting stroke recovery. A clinical trial to assess the safety, feasibility, and efficacy among patients with stroke is warranted.

ObjectiveSocioeconomic status (SES) and lifestyle activities (LA) are strongly related, and both are associated with dementia risk. We investigated the influence of SES and LA on brain atrophy and cognitive decline considering amyloid‐beta (Aβ) positron emission tomography and white matter hyperintensity (WMH) load.MethodsWe investigated 221 older adults (mean age, 67.1 ± 8.2 years) who underwent cognitive testing annually over a median follow‐up period of 3.4 years. Longitudinal T1‐weighted magnetic resonance imaging was available for 181 participants. Measures of SES and LA were collected using questionnaires and combined to SES and LA scores using a latent variable approach. We used linear mixed‐effects models to investigate if SES and LA are independently or interactively with Aβ and WMH load associated with decline in domains language, processing speed/attention, executive function, and episodic memory. Mediation models assessed whether these associations were explained by gray matter atrophy.ResultsSES and LA were associated with better cognitive performance at baseline, but were not associated with cognitive decline over time. In interaction with brain pathologies, higher LA reduced the detrimental effects of Aβ and WMH load on language decline, whereas higher SES reduced the detrimental effects of Aβ pathology on episodic memory decline. Individuals with low SES showed faster Aβ‐related gray matter atrophy, which mediated the association between Aβ and episodic memory decline but not language decline.InterpretationThese results suggest that multiple resilience mechanisms underlie the protective effects of SES and LA on cognitive decline. Interventions targeting SES‐related risk factors may be most effective when implemented early, before neurodegenerative changes begin. ANN NEUROL 2025;98:1222–1236

The establishment of the body plan during gastrulation represents a hallmark of animal life. It emerges from the interplay of gene-regulatory programs and positional cues, yet how these signals are integrated post-transcriptionally remains largely unexplored. Here, we combine the scalability of mouse gastruloids with a single-cell CRISPR screening platform to functionally dissect germ layer specification at single-cell transcriptomic resolution. Focusing on post-transcriptional regulation, we systematically map drivers of mesodermal and endodermal fate and identify the deadenylase Cnot8. Loss of Cnot8 leads to widespread poly(A) tail elongation and transcript stabilization, shifting mesoderm differentiation toward ectopic notochord fate, thereby profoundly impacting axial patterning. Collectively, our findings identify mRNA deadenylation as a fundamental mechanism linking cellular identity with morphogenetic signaling during mammalian body plan formation.

Abstract This paper investigates whether the systematic application of open strategy can align goals in emerging public‐private hybrid organizations, which face the challenge of integrating different identities, forms, and rationales from both public and private stakeholders. We develop an evaluative framework, addressing three crucial issues for a public‐private hybrid's early development: What is the public‐private hybrid's purpose? Who are the strategic actors involved? What knowledge and skills are needed? By applying the framework to a qualitative case study from the field of Swiss innovation policy, we learn that inclusiveness and transparency largely depend on the timeline of a hybrid's emergence. Public‐private hybrids can either choose an inclusive, transparent but gradual, and slow strategy process or a speedy process characterized by the traditional ‘management at the top’ approach. This study offers both empirical and theoretical insights into strategy development in public‐private hybrid organizations and its significance for public policy implementation.

CRISPR-based genome editing of pseudogene-associated disorders, such as p47phox-deficient chronic granulomatous disease (p47 CGD), is challenged by chromosomal rearrangements due to presence of multiple targets. We report that interactions between highly homologous sequences that are localized on the same chromosome contribute substantially to post-editing chromosomal rearrangements. We successfully employed editing approaches at the NCF1 gene and its pseudogenes, NCF1B and NCF1C, in a human cell line model of p47 CGD and in patient-derived human hematopoietic stem and progenitor cells. Upon genetic engineering, a droplet digital PCR-based method identified cells with altered copy numbers, spanning megabases from the edited loci. We attributed the high aberration frequency to the interaction between repetitive sequences and their predisposition to recombination events. Our findings emphasize the need for careful evaluation of the target-specific genomic context, such as the presence of homologous regions, whose instability can constitute a risk factor for chromosomal rearrangements upon genome editing.

Facial hyperpigmentation is a highly prevalent dermatological condition, characterized by dark spots on the skin resulting from excess melanin production. Hyperpigmentation significantly impacts patients’ quality of life and self-esteem. Current treatments often present disadvantages linked to poor product tolerability. A topical cosmetic approach combining three lightening active ingredients (tranexamic acid, niacinamide, vitamin C) offers a new option for treating dark spots on the skin. The present in-use test under dermatological control evaluated the clinical safety and efficacy of a cream and serum containing these three ingredients, formulated with hyaluronic acid for enhanced delivery, stability, and efficacy. A total of 22 Caucasian patients with facial hyperpigmentation, both male and female, aged between 45 and 67 years, applied the cream and serum for 8 weeks. Clinical assessments, colorimetric evaluations, standardized photography, and self-assessment questionnaires were used to measure outcomes. No serious adverse effects were recorded, and the incidence of local adverse effects was low, highlighting good tolerability of the investigated test items. In most participants, significant improvements in hyperpigmented areas were recorded. Clinical scoring by the dermatologist investigator indicated a statistically significant 13% reduction in color intensity and a 6% reduction in the size of dark spots after 8 weeks of treatment. Colorimetric evaluation showed a statistically significant 1% increase in luminosity (L* parameter) and an 8% improvement in the Individual Typological Angle (ITA°) in endpoint, indicating lighter skin spots. Subjective assessments reflected high user satisfaction, with 95% of participants noting improvements in skin hydration and luminosity, and 77% reporting a reduced appearance of dark spots. Overall, the present work supports the use of tranexamic acid, niacinamide, and vitamin C as an effective and well-tolerated combined topical management option for hyperpigmentation. This combination offers a viable alternative to classical whiteners for individuals seeking to reduce facial skin coloration imbalance and improve skin tone.

Abnormal alpha-synuclein (αSyn) and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim to visualize αSyn inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. The fluorescent pyrimidoindole derivative THK-565 probe was characterized by means of recombinant fibrils and brains from 10- to 11-month-old M83 mice. Concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging were subsequently performed in vivo. Structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 T as well as scanning transmission x-ray microscopy (STXM) were performed to characterize the iron deposits in the perfused brains. Immunofluorescence and Prussian blue staining were further performed on brain slices to validate the detection of αSyn inclusions and iron deposition. THK-565 showed increased fluorescence upon binding to recombinant αSyn fibrils and αSyn inclusions in post-mortem brain slices from patients with PD and M83 mice. Administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 min post-intravenous injection by wide-field fluorescence compared to nontransgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. In conclusion, we demonstrated in vivo mapping of αSyn by means of noninvasive epifluorescence and vMSOT imaging and validated the results by targeting the THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo.

PurposeNon-obstructive azoospermia (NOA) is a common, but complex problem, with multiple therapeutic options and a lack of clear guidelines. Hence, there is considerable controversy and marked variation in the management of NOA. This survey evaluates contemporary global practices related to medical and surgical management for patients with NOA.Materials and MethodsA 56-question online survey covering various aspects of the evaluation and management of NOA was sent to specialists around the globe. This paper analyzes the results of the second half of the survey dealing with the management of NOA. Results have been compared to current guidelines, and expert recommendations have been provided using a Delphi process.ResultsParticipants from 49 countries submitted 336 valid responses. Hormonal therapy for 3 to 6 months was suggested before surgical sperm retrieval (SSR) by 29.6% and 23.6% of participants for normogonadotropic hypogonadism and hypergonadotropic hypogonadism respectively. The SSR rate was reported as 50.0% by 26.0% to 50.0% of participants. Interestingly, 46.0% reported successful SSR in <10% of men with Klinefelter syndrome and 41.3% routinely recommended preimplantation genetic testing. Varicocele repair prior to SSR is recommended by 57.7%. Half of the respondents (57.4%) reported using ultrasound to identify the most vascularized areas in the testis for SSR. One-third proceed directly to microdissection testicular sperm extraction (mTESE) in every case of NOA while others use a staged approach. After a failed conventional TESE, 23.8% wait for 3 months, while 33.1% wait for 6 months before proceeding to mTESE. The cut-off of follicle-stimulating hormone for positive SSR was reported to be 12–19 IU/mL by 22.5% of participants and 20–40 IU/mL by 27.8%, while 31.8% reported no upper limit.ConclusionsThis is the largest survey to date on the real-world medical and surgical management of NOA by reproductive experts. It demonstrates a diverse practice pattern and highlights the need for evidence-based international consensus guidelines.