A Phase 1/1b, Three-Part, Randomised, Placebo-Controlled, Single- and Multiple-Ascending-Dose Studyto Evaluate the Safety, Pharmacokinetics, and Activity of SZN-1326 in Healthy Volunteers and in Subjects with Moderate to Severe Ulcerative Colitis

开始日期2022-05-09

申办/合作机构

Surrozen Operating, Inc.初创企业

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100 项与 LRP6 x FZD5 相关的临床结果

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100 项与 LRP6 x FZD5 相关的转化医学

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0 项与 LRP6 x FZD5 相关的专利（医药）

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项与 LRP6 x FZD5 相关的文献（医药）

2024-03-01·Development

Exploiting spatiotemporal regulation of FZD5 during neural patterning for efficient ventral midbrain specification

Article

作者: Pauli, Quinn ; Adams, Jarrett J. ; Blazer, Levi L. ; Bonin, Robert ; Russo, Emma ; Goeva, Aleksandrina ; Angers, Stephane ; Yang, Andy ; Salahpour, Ali ; Chidiac, Rony ; Sidhu, Sachdev S. ; Steenland, Hendrik

ABSTRACTThe Wnt/β-catenin signaling governs anterior-posterior neural patterning during development. Current human pluripotent stem cell (hPSC) differentiation protocols use a GSK3 inhibitor to activate Wnt signaling to promote posterior neural fate specification. However, GSK3 is a pleiotropic kinase involved in multiple signaling pathways and, as GSK3 inhibition occurs downstream in the signaling cascade, it bypasses potential opportunities for achieving specificity or regulation at the receptor level. Additionally, the specific roles of individual FZD receptors in anterior-posterior patterning are poorly understood. Here, we have characterized the cell surface expression of FZD receptors in neural progenitor cells with different regional identity. Our data reveal unique upregulation of FZD5 expression in anterior neural progenitors, and this expression is downregulated as cells adopt a posterior fate. This spatial regulation of FZD expression constitutes a previously unreported regulatory mechanism that adjusts the levels of β-catenin signaling along the anterior-posterior axis and possibly contributes to midbrain-hindbrain boundary formation. Stimulation of Wnt/β-catenin signaling in hPSCs, using a tetravalent antibody that selectively triggers FZD5 and LRP6 clustering, leads to midbrain progenitor differentiation and gives rise to functional dopaminergic neurons in vitro and in vivo.

2023-05-30·Cells

β-Catenin Elicits Drp1-Mediated Mitochondrial Fission Activating the Pro-Apoptotic Caspase-1/IL-1β Signalosome in Aeromonas hydrophila-Infected Zebrafish Macrophages.

Article

作者: Mazumder, Shibnath ; Kumar, Manmohan ; Kumar, Jai ; Sharma, Shagun

Canonical Wnt signaling plays a major role in regulating microbial pathogenesis. However, to date, its involvement in A. hydrophila infection is not well known. Using zebrafish (Danio rerio) kidney macrophages (ZKM), we report that A. hydrophila infection upregulates wnt2, wnt3a, fzd5, lrp6, and β-catenin (ctnnb1) expression, coinciding with the decreased expression of gsk3b and axin. Additionally, increased nuclear β-catenin protein accumulation was observed in infected ZKM, thereby suggesting the activation of canonical Wnt signaling in A. hydrophila infection. Our studies with the β-catenin specific inhibitor JW67 demonstrated β-catenin to be pro-apoptotic, which initiates the apoptosis of A. hydrophila-infected ZKM. β-catenin induces NADPH oxidase (NOX)-mediated ROS production, which orchestrates sustained mitochondrial ROS (mtROS) generation in the infected ZKM. Elevated mtROS favors the dissipation of the mitochondrial membrane potential (ΔΨ_m) and downstream Drp1-mediated mitochondrial fission, leading to cytochrome c release. We also report that β-catenin-induced mitochondrial fission is an upstream regulator of the caspase-1/IL-1β signalosome, which triggers the caspase-3 mediated apoptosis of the ZKM as well as A. hydrophila clearance. This is the first study suggesting a host-centric role of canonical Wnt signaling pathway in A. hydrophila pathogenesis wherein β-catenin plays a primal role in activating the mitochondrial fission machinery, which actively promotes ZKM apoptosis and helps in containing the bacteria.

2023-03-01·Nature Reviews Neurology

WNT receptor variant linked to synaptic degeneration

Article

作者: Wood, Heather

A review.A genetic variant of the WNT receptor LRP6 exacerbates synapse degeneration in mouse models of ageing and Alzheimers disease, according to new research.The LRP6-Val variant, which results in replacement of isoleucine with valine at amino acid 1062 of LRP6, is associated with late-onset AD, and the findings provide clues to the mechanisms that could underlie this relationship.To explore the effects of LRP6-Val in vivo, the researchers used CRISPR-Cas9 genome editing to generate a Lrp6-val knock-in mouse line.Mice that carried this variant initially developed normally but showed progressive structural and functional synaptic defects with age. Neurons from these mice failed to respond to WNT7a, which normally acts through a Frizzled 5-LRP6 receptor complex.Neurons from these mice failed to respond to WNT7a, which normally acts through a Frizzled 5-LRP6 receptor complex to promote the assembly of synapses.The investigators also crossed Lrp6-val mice with the NL-G-F mouse model of AD. The resulting NL-G-F Lrp6-val mice showed exacerbation of synapse loss around amyloid-β plaques in the brain.The resulting NL-G-F Lrp6-val mice showed exacerbation of synapse loss around amyloid-β plaques in the brain.

项与 LRP6 x FZD5 相关的新闻（医药）

2024-01-18

·Firstwordpharma

Surrozen switches gears, halting SZN-1326 in inflammatory bowel disease

Surrozen announced it will stop developing SZN-1326 for inflammatory bowel disease (IBD) after running into challenges finding a safe and effective dose in a Phase I trial. The news shaved off about 4% of its stock price on Thursday.The bi-specific antibody modulates Wnt signaling in target tissue by binding to particular Frizzled and LRP receptors that are highly expressed in intestinal crypts. Surrozen has said that SZN-1326 demonstrated repair of damaged intestinal epithelium and anti-inflammatory effects in preclinical models.Elevated transaminase levelsSurrozen's decision to drop the IBD programme follows the completion of a Phase I single ascending dose trial involving 37 healthy volunteers. The company said it struggled to identify an ideal dose of the drug after several participants at higher dose levels experienced asymptomatic liver enzyme increases, including four who had Grade 3 ALT and AST elevations.There were no other clinically significant lab abnormalities, and the transaminase elevations resolved spontaneously, but Surrozen had already reported that three of the four subjects had Grade 3 ALT and AST elevations back in 2022."While no safety signal was observed at lower doses, lower-dose levels would not be expected to activate Wnt signaling and produce a pharmacologic effect in the intestine," the company noted in its statement Thursday. It also pointed to broader strategic considerations, such as significant clinical development expenses and market competition in IBD.Prioritising liver disease candidateThe company said it will instead now concentrate on another investigational treatment, SZN-043 for severe liver diseases, starting with alcohol-associated hepatitis. The compound, a hepatocyte targeted R-spondin-mimetic, is designed to stimulate the regeneration of liver cells in patients with liver disease.Results from a Phase Ia trial in patients with chronic liver disease and in healthy volunteers are due this quarter. The company expects to begin enrolling patients with alcohol-associated hepatitis in a Phase Ib study this year, and says proof-of-concept data could be available in the second half. Surrozen is also co-developing SZN-413 with Boehringer Ingelheim as a potential treatment for retinal vascular-associated diseases. The companies joined forces on the drug in 2022 under a deal worth potentially over $586.5 million.

临床1期临床结果临床2期蛋白降解靶向嵌合体