進行性白質脳症

Polypharmacology is dedicated to the development of compounds acting on at least two targets (multi-target-directed ligands, MTDLs). In 2025, the European Medicines Agency (EMA) approved 38 drugs, and 11 out of them were MTDLs. Most of them are antibody-drug conjugates, bispecific antibodies, or kinase inhibitors, all of which are indicated for tumor treatment, including datopotamab deruxtecan (hormone receptor-positive, HER2-negative breast cancer), tisotumab vedotin (advanced cervical carcinoma), linvoseltamab (fourth-line treatment of multiple myeloma), and erdafitinib (advanced urothelial carcinoma). The small molecule tiratricol is an orphan drug, which is indicated for the treatment of the very rare Allan-Herndon-Dudley syndrome. The second part of the present review is dedicated to the post-marketing safety surveillance of MTDLs approved by the EMA in 2022-2024. For 19 out of the 27 MTDLs, which are still available on the European market, comprehensive pharmacovigilance studies, mainly based on the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), were found. New safety signals have been identified, including Stevens-Johnson syndrome and progressive multifocal leukoencephalopathy. The analysis also revealed a more favorable safety profile of the MTDL tirzepatide (a dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide analogue) compared to the single-targeted drug semaglutide (glucagon-like peptide-1 analogue), including lower reporting rates of acute kidney injury and no significant suicidality signal.

This case report describes progressive multifocal leukoencephalopathy in a patient with ADA-SCID status after gene therapy. Persistent metabolic dysfunction likely contributed to JC virus reactivation, highlighting this rare complication of ADA-SCID and incomplete reconstitution seen with early protocols.

Background: Aicardi-Goutières syndrome (AGS) is a neurogenetic leukoencephalopathy that typically manifests within the first 6 months of life. Classically, AGS presents with an early encephalopathic episode characterised by feeding difficulties, irritability and psychomotor regression or delay. Cutaneous lesions affecting the extremities and epilepsy are common, with symptoms usually evolving over weeks to months before stabilising. Milder phenotypes have been described, often demonstrating relative preservation of language and cognitive function. Case presentation: Here, we report a case of a 31-year-old woman with compound heterozygous variants in the ADAR gene: (GRCh38) NM_001111.4:c.577C>G p.(Pro193Ala) and (GRCh38) NM_001111.4:c.1111_1112del p.(Ser371Cysfs*3), consistent with AGS. The developmental history revealed normal early motor milestones. At age 3, she developed progressive ataxia and hypotonia. Over time, she exhibited spasticity, dystonia and learning difficulties, along with significant cardiac valvular calcification. Conclusions: The patient was recently referred for consideration of treatment with baricitinib, a selective JAK1/JAK2 inhibitor. This case underscores the importance of considering AGS in individuals with non-classical presentations, particularly when extracerebral calcification is a notable feature.

Cytomegalovirus (CMV) infection in the extremely preterm infant represents a major diagnostic challenge: its clinical manifestations overlap with comorbidities inherent to prematurity, underlying immunodeficiency may suppress viral replication below detectable thresholds, and the diagnostic window for confirming congenital infection closes irreversibly at 21 days of life. An extremely preterm female infant (26 weeks, 800 g) had a neonatal course complicated by bronchopulmonary dysplasia, leukoencephalopathy, and chorioretinitis - findings that, individually, were attributable to prematurity. CMV was not tested within the 21-day diagnostic window. A plasma CMV PCR at day 44, triggered by clinical deterioration, returned negative. At 70 days of life, severe multilobar pneumonia with respiratory failure requiring high-frequency oscillatory ventilation developed without an identifiable bacterial aetiology. Targeted bronchoalveolar lavage confirmed CMV at 136,000 IU/mL, markedly dissociated from simultaneous plasma viraemia of 9,910 IU/mL. Primary combined immunodeficiency (T⁻/B⁺/NK⁺ pattern) was diagnosed simultaneously. Ganciclovir therapy achieved progressive viral load reduction. In the extremely preterm infant, CMV may remain clinically invisible behind more immediate diagnoses. A negative plasma CMV PCR does not exclude active infection in the setting of combined immunodeficiency. Severe multisystem deterioration without an identified aetiology should prompt site-directed CMV investigation and simultaneous immunological evaluation.

Vascular dementia (VD) is a common cognitive impairment syndrome, for which there is currently no effective treatment. As a distinctive acupuncture therapy founded by Professor Jin Rui, the intelligence three-needling (Zhisanzhen, a specific set of 3 acupuncture points) selects the acupoints Shenting (GV24) and bilateral Benshen (GB13), and has shown significant clinical efficacy in improving cognitive function in patients with vascular dementia. This article systematically reviewed the research progress of intelligence three-needling in treating vascular dementia from both clinical and mechanistic perspectives: (1) Clinically, intelligence three-needling, applied via manual acupuncture or electroacupuncture, either alone or in combination with medication and rehabilitation training, can effectively improve patients' scores on the Mini-Mental State Examination and Hasegawa Dementia Scale, as well as their daily living abilities. (2) Mechanistically, intelligence three-needling exerts multi-target and multi-pathway neuroprotective effects, including reducing neurotoxic substances such as homocysteine and β-amyloid, inhibiting neuroinflammatory responses, modulating synaptic plasticity-related proteins, improving cerebral blood flow perfusion, and promoting neuronal repair and functional recovery by regulating the Eph/ephrin signaling pathway and GABAergic system.