Hemophilia is a rare monogenic inherited coagulation factor deficiency disease,which begins in early childhood,and severe patients often have a history of spontaneous bleeding or joint muscle bleeding,requiring long-term frequent transfusion of clotting factor.This article reviews the clinical development process of bispecific antibody drug EMICIZUMAB and two gene therapies ROCTAVIAN and HEMGENIX for the corresponding hemophilia subtypes,so as to summarize the strategies for rare disease drug development and the key elements of gene therapy drug development,and to provide reference for the development of similar drugs in similar indications in the future.

Background: and Purpose Limited evidence exists on the effectiveness of endovascular treatment (EVT) for acute posterior circulation tandem lesion (PCTL). This study aimed to explore the role of extracranial vertebral artery (VA) stenting in patients with PCTL stroke undergoing EVT. Methods: Individual patient data were pooled from the BASILAR (EVT for Acute Basilar Artery Occlusion Study) and PERSIST (Posterior Circulation Ischemic Stroke) registries. Patients with PCTLs who underwent EVT were included in the present cohort and divided into the stenting and nonstenting groups based on the placement of extracranial VA stents. The primary efficacy outcome was the modified Rankin Scale (mRS) scores at 90 days and 1 year. Safety outcomes included 24-hour symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days and 1 year post-surgery. Results: A combined dataset of 1,320 patients with posterior circulation artery occlusion, including 263 (19.9%) with tandem lesions, of whom 217 (median age, 65 years; 82.9% male) met the inclusion criteria for the analysis. The stenting group had 84 (38.7%) patients, while the non-stenting group had 133 (61.3%). After adjustment for the potential confounders, extracranial VA stenting was associated with favorable shifts in mRS scores at both 90 days (adjusted common odds ratio [OR], 2.30; 95% confidence interval [CI], 1.23–4.28; P<0.01) and 1 year (adjusted OR [aOR], 2.04; 95% CI [1.05–3.97]; P=0.04), along with lower rate of mortality at both 90 days (aOR, 0.45; 95% CI [0.21–0.93]; P=0.01) and 1 year (aOR, 0.36; 95% CI [0.16–0.79]; P=0.01), with no significant difference in sICH incidence (aOR, 0.35; 95% CI [0.06–1.98]; P=0.24). Conclusion Extracranial VA stenting during EVT may improve functional outcomes and reduce mortality in patients with PCTL strokes.

This study explored the potential therapeutic targets and mechanisms of Danggui Shaoyao San(DSS) in the prevention and treatment of Alzheimer's disease(AD) through transcriptomics and metabolomics, combined with animal experiments. Fifty male C57BL/6J mice, aged seven weeks, were randomly divided into the following five groups: control, model, positive drug, low-dose DSS, and high-dose DSS groups. After the intervention, the Morris water maze was used to assess learning and memory abilities of mice, and Nissl staining and hematoxylin-eosin(HE) staining were performed to observe pathological changes in the hippocampal tissue. Transcriptomics and metabolomics were employed to sequence brain tissue and identify differential metabolites, analyzing key genes and metabolites related to disease progression. Reverse transcription-quantitative polymerase chain reaction(RT-qPCR) was employed to validate the expression of key genes. The Morris water maze results indicated that DSS significantly improved learning and cognitive function in scopolamine(SCOP)-induced model mice, with the high-dose DSS group showing the best results. Pathological staining showed that DSS effectively reduced hippocampal neuronal damage, increased Nissl body numbers, and reduced nuclear pyknosis and neuronal loss. Transcriptomics identified seven key genes, including neurexin 1(Nrxn1) and sodium voltage-gated channel α subunit 1(Scn1a), and metabolomics revealed 113 differential metabolites, all of which were closely associated with synaptic function, oxidative stress, and metabolic regulation. RT-qPCR experiments confirmed that the expression of these seven key genes was consistent with the transcriptomics results. This study suggests that DSS significantly improves learning and memory in SCOP model mice and alleviates hippocampal neuronal pathological damage. The mechanisms likely involve the modulation of synaptic function, reduction of oxidative stress, and metabolic balance, with these seven key genes serving as important targets for DSS in the treatment of AD.
Animals ; Alzheimer Disease/genetics* ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Mice, Inbred C57BL ; Metabolomics ; Transcriptome/drug effects* ; Maze Learning/drug effects* ; Hippocampus/metabolism* ; Humans ; Disease Models, Animal ; Memory/drug effects*

Background: and Purpose Limited evidence exists on the effectiveness of endovascular treatment (EVT) for acute posterior circulation tandem lesion (PCTL). This study aimed to explore the role of extracranial vertebral artery (VA) stenting in patients with PCTL stroke undergoing EVT. Methods: Individual patient data were pooled from the BASILAR (EVT for Acute Basilar Artery Occlusion Study) and PERSIST (Posterior Circulation Ischemic Stroke) registries. Patients with PCTLs who underwent EVT were included in the present cohort and divided into the stenting and nonstenting groups based on the placement of extracranial VA stents. The primary efficacy outcome was the modified Rankin Scale (mRS) scores at 90 days and 1 year. Safety outcomes included 24-hour symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days and 1 year post-surgery. Results: A combined dataset of 1,320 patients with posterior circulation artery occlusion, including 263 (19.9%) with tandem lesions, of whom 217 (median age, 65 years; 82.9% male) met the inclusion criteria for the analysis. The stenting group had 84 (38.7%) patients, while the non-stenting group had 133 (61.3%). After adjustment for the potential confounders, extracranial VA stenting was associated with favorable shifts in mRS scores at both 90 days (adjusted common odds ratio [OR], 2.30; 95% confidence interval [CI], 1.23–4.28; P<0.01) and 1 year (adjusted OR [aOR], 2.04; 95% CI [1.05–3.97]; P=0.04), along with lower rate of mortality at both 90 days (aOR, 0.45; 95% CI [0.21–0.93]; P=0.01) and 1 year (aOR, 0.36; 95% CI [0.16–0.79]; P=0.01), with no significant difference in sICH incidence (aOR, 0.35; 95% CI [0.06–1.98]; P=0.24). Conclusion Extracranial VA stenting during EVT may improve functional outcomes and reduce mortality in patients with PCTL strokes.

Hemophilia is a rare monogenic inherited coagulation factor deficiency disease,which begins in early childhood,and severe patients often have a history of spontaneous bleeding or joint muscle bleeding,requiring long-term frequent transfusion of clotting factor.This article reviews the clinical development process of bispecific antibody drug EMICIZUMAB and two gene therapies ROCTAVIAN and HEMGENIX for the corresponding hemophilia subtypes,so as to summarize the strategies for rare disease drug development and the key elements of gene therapy drug development,and to provide reference for the development of similar drugs in similar indications in the future.

Background: and Purpose Limited evidence exists on the effectiveness of endovascular treatment (EVT) for acute posterior circulation tandem lesion (PCTL). This study aimed to explore the role of extracranial vertebral artery (VA) stenting in patients with PCTL stroke undergoing EVT. Methods: Individual patient data were pooled from the BASILAR (EVT for Acute Basilar Artery Occlusion Study) and PERSIST (Posterior Circulation Ischemic Stroke) registries. Patients with PCTLs who underwent EVT were included in the present cohort and divided into the stenting and nonstenting groups based on the placement of extracranial VA stents. The primary efficacy outcome was the modified Rankin Scale (mRS) scores at 90 days and 1 year. Safety outcomes included 24-hour symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days and 1 year post-surgery. Results: A combined dataset of 1,320 patients with posterior circulation artery occlusion, including 263 (19.9%) with tandem lesions, of whom 217 (median age, 65 years; 82.9% male) met the inclusion criteria for the analysis. The stenting group had 84 (38.7%) patients, while the non-stenting group had 133 (61.3%). After adjustment for the potential confounders, extracranial VA stenting was associated with favorable shifts in mRS scores at both 90 days (adjusted common odds ratio [OR], 2.30; 95% confidence interval [CI], 1.23–4.28; P<0.01) and 1 year (adjusted OR [aOR], 2.04; 95% CI [1.05–3.97]; P=0.04), along with lower rate of mortality at both 90 days (aOR, 0.45; 95% CI [0.21–0.93]; P=0.01) and 1 year (aOR, 0.36; 95% CI [0.16–0.79]; P=0.01), with no significant difference in sICH incidence (aOR, 0.35; 95% CI [0.06–1.98]; P=0.24). Conclusion Extracranial VA stenting during EVT may improve functional outcomes and reduce mortality in patients with PCTL strokes.

Depression is a heterogeneous mental disorder in which the interaction between genetic susceptibility and environ-mental factors plays a key role in its pathogenesis.Although the specific mechanisms of the disease still need to be thoroughly studied and elucidated,there is now a broad consensus that epi-genetic markers have a central influence on its mechanism of ac-tion.DNA methylation of brain-derived neurotrophic factor(BD-NF)is not only regarded as a promising epigenetic biomarker of pathology,but may also help predict the efficacy of antidepres-sants.In this paper we reviewed the gene structure of BDNF and its DNA methylation regulation mechanism,and also analyzed the changes of DNA methylation of this factor in depression pa-tients and animal models,aiming to provide new ideas and theo-retical support for clinical research.

Depression is a heterogeneous mental disorder in which the interaction between genetic susceptibility and environ-mental factors plays a key role in its pathogenesis.Although the specific mechanisms of the disease still need to be thoroughly studied and elucidated,there is now a broad consensus that epi-genetic markers have a central influence on its mechanism of ac-tion.DNA methylation of brain-derived neurotrophic factor(BD-NF)is not only regarded as a promising epigenetic biomarker of pathology,but may also help predict the efficacy of antidepres-sants.In this paper we reviewed the gene structure of BDNF and its DNA methylation regulation mechanism,and also analyzed the changes of DNA methylation of this factor in depression pa-tients and animal models,aiming to provide new ideas and theo-retical support for clinical research.

AIM To investigate the clinical effects of Tongdu Huoxue Decoction on patients with cervical spondylosis of vertebral artery type.METHODS Eighty-five patients were randomly assigned into control group (44 cases) for 14-day administration of Betahistine Hydrochloride Tablets,and observation group (41 cases) for 14-day administration of both Tongdu Huoxue Decoction and Tongdu Huoxue Decoction.The changes in clinical effects,hemorheological indices ( vertebral artery resistance index,vertebral artery systolic blood flow velocity,vertebral artery diastolic blood flow velocity),TCM syndrome scores,disease-related serum indices ( NSE,NPY,NF-κB),cervical motion indices ( flexion and extension range of motion,cervical curvature,horizontal vertebral displacement),hemodynamic indices ( whole blood high shear viscosity,whole blood low shear viscosity,plasma viscosity) and incidence of adverse reactions were detected.RESULTS The observation group demonstrated higher total effective rate than the control group ( P<0.05 ).After the treatment,the two groups displayed decreased vertebral artery resistance index,disease-related serum indices,TCM syndrome scores,horizontal vertebral displacement,hemodynamic indices ( P<0.05 ),and increased vertebral artery systolic blood flow velocity,vertebral artery diastolic blood flow velocity,flexion and extension range of motion,cervical curvature ( P<0.05 ),especially for the observation group ( P<0.05 ).No significant difference in incidence of adverse reactions was found between the two groups (P>0.05).CONCLUSION For the patients with cervical spondylosis of vertebral artery type,Tongdu Huoxue Decoction can safely and effectively improve TCM syndrome scores and cervical motion,whose mechanisms may contribute to the regulation of hemorheology,hemodynamics and disease-related serum indices.

AIM To investigate the clinical effects of Tongdu Huoxue Decoction on patients with cervical spondylosis of vertebral artery type.METHODS Eighty-five patients were randomly assigned into control group (44 cases) for 14-day administration of Betahistine Hydrochloride Tablets,and observation group (41 cases) for 14-day administration of both Tongdu Huoxue Decoction and Tongdu Huoxue Decoction.The changes in clinical effects,hemorheological indices ( vertebral artery resistance index,vertebral artery systolic blood flow velocity,vertebral artery diastolic blood flow velocity),TCM syndrome scores,disease-related serum indices ( NSE,NPY,NF-κB),cervical motion indices ( flexion and extension range of motion,cervical curvature,horizontal vertebral displacement),hemodynamic indices ( whole blood high shear viscosity,whole blood low shear viscosity,plasma viscosity) and incidence of adverse reactions were detected.RESULTS The observation group demonstrated higher total effective rate than the control group ( P<0.05 ).After the treatment,the two groups displayed decreased vertebral artery resistance index,disease-related serum indices,TCM syndrome scores,horizontal vertebral displacement,hemodynamic indices ( P<0.05 ),and increased vertebral artery systolic blood flow velocity,vertebral artery diastolic blood flow velocity,flexion and extension range of motion,cervical curvature ( P<0.05 ),especially for the observation group ( P<0.05 ).No significant difference in incidence of adverse reactions was found between the two groups (P>0.05).CONCLUSION For the patients with cervical spondylosis of vertebral artery type,Tongdu Huoxue Decoction can safely and effectively improve TCM syndrome scores and cervical motion,whose mechanisms may contribute to the regulation of hemorheology,hemodynamics and disease-related serum indices.