Last update 01 Nov 2024

PBGD

Last update 01 Nov 2024

Basic Info

Synonyms

HMBS, Hydroxymethylbilane synthase, PBG-D

+ [8]

Introduction

As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen (PubMed:18936296, PubMed:19138865, PubMed:23815679). Catalysis begins with the assembly of the dipyrromethane cofactor by the apoenzyme from two molecules of porphobilinogen or from preuroporphyrinogen. The covalently linked cofactor acts as a primer, around which the tetrapyrrole product is assembled. In the last step of catalysis, the product, preuroporphyrinogen, is released, leaving the cofactor bound to the holodeaminase intact (PubMed:18936296).

Drugs associated with PBGD

rhApoAI-PBGD

Target

PBGD

Mechanism

PBGD modulators

Active Org.

University of Navarra

Originator Org.

University of Navarra

Active Indication

Porphyrias

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

rApoAI-PBGDms

Target

PBGD

Mechanism

PBGD stimulants

Active Org.

Navarre Biomedical Ltd. [+2]

Originator Org.

Moderna, Inc. [+2]

Active Indication

Porphyrias

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

RAG-05

Target

PBGD

Mechanism

PBGD stimulants

Active Org.

Ractigen TherapeuticsStartup

Originator Org.

Ractigen TherapeuticsStartup

Active Indication

Porphyria, Acute Intermittent

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with PBGD

NCT02082860 / CompletedPhase 1

Phase I, Multicentre, Open Label, Single Dose, Dose-ranging Clinical Trial to Investigate the Safety and Tolerability of a Gene Therapy rAAV2/5-PBGD for the Treatment of Acute Intermittent Porphyria

This is a Phase I trial aimed to determine the safety of the investigational gene therapy product (rAAV2/5-PBGD) for the treatment of Acute Intermittent Porphyria (AIP).
Up to eight patients fulfilling the eligibility criteria will participate in this multicentre, open label, single dose, dose-ranging Phase I clinical trial.
The enrolled patients will be followed up to assess the safety profile of the investigational gene therapy product and to establish the maximum therapeutic safe dose to be administered in future confirmatory/pivotal clinical trial(s). In addition, the biological and clinical response to the treatment with rAAV2/5-PBGD in AIP patients will be assessed.
A complete evaluation of the clinical (symptoms and quality of life assessment) and laboratory (blood and urine) data will be performed.

Start Date01 Nov 2012

Sponsor / Collaborator

Digna Biotech SL

[+2]

100 Clinical Results associated with PBGD

100 Translational Medicine associated with PBGD

0 Patents (Medical) associated with PBGD

2,701

Literatures (Medical) associated with PBGD

01 Mar 2025·Biomaterials

Ultra-pH-sensitive nanoplatform for precise tumor therapy

Review

Author: Li, Shijie ; Ling, Jue ; Qin, Yuling ; Zhang, Ke ; Li, Jiaying ; Zhou, Xiaobo ; Li, Wu ; Wu, Li

The emergence of precision cancer treatment has triggered a paradigm shift in the field of oncology, facilitating the implementation of more effective and personalized therapeutic approaches that enhance patient outcomes. The pH of the tumor microenvironment (TME) plays a pivotal role in both the initiation and progression of cancer, thus emerging as a promising focal point for precision cancer treatment. By specifically targeting the acidic conditions inherent to the tumor microenvironment, innovative therapeutic interventions have been proposed, exhibiting significant potential in augmenting treatment efficacy and ameliorating patient prognosis. The concept of ultra-pH-sensitive (UPS) nanoplatform was proposed several years ago, demonstrating exceptional pH sensitivity and an adjustable pH transition point. Subsequently, diverse UPS nanoplatforms have been actively explored for biomedical applications, enabling the loading of fluorophores, therapeutic drugs, and photosensitizers. This review aims to elucidate the design strategy and response mechanism of the UPS nanoplatform, with a specific emphasis on its applications in surgical therapy, immunotherapy, drug delivery, photodynamic therapy, and photothermal therapy. The potential and challenges of translating in the clinic on UPS nanoplatforms are finally explored. Thanks to its responsive and easily modifiable nature, the integration of multiple functional units within a UPS nanoplatform holds great promise for future advancements in tumor precision theranositcs.

01 Dec 2024·Life Sciences

Inhibition of proteasome activity facilitates definitive endodermal specification of pluripotent stem cells by influencing YAP signalling

Article

Author: Kumar, Anujith ; Prasanna, Jyothi ; Bhaskar, Smitha ; Kalathur, Guruprasad ; Ashok, Akshaya ; Ashwathnarayan, Ashwini ; Shekar, Spandana

AIMSThe knowledge of the molecular players that regulate the generation of endoderm cells is imperative to obtain homogenous population of pancreatic β-cells from stem cells. The Ubiquitin proteasome system (UPS) has been envisaged as a crucial intracellular protein degradation system, but its role in the generation of β-cells remains elusive. Hence, it would be appropriate to unravel the potential role of UPS in endoderm specification and utilize the understanding to generate β-cells from pluripotent stem cells.MATERIALS AND METHODSThe pluripotent stem cells (mESCs, miPSCs and hIPSCs) were subjected to differentiation towards pancreatic β-cells and assessed the proteasomal activity during endodermal differentiation. Pharmacologic agents MG132 and IU-1 were employed to inhibit and activate proteasomal activity respectively at the definitive endoderm stage to investigate its impact on the generation of β-cells. The expression of stage-specific genes were analyzed at transcript and protein levels. We also explored the role of unfolded protein response and UPS-regulated signalling pathways in endodermal differentiation.KEY FINDINGSWe observed decreased proteasomal activity specifically during endoderm, but not during the generation of other lineages. Extraneous proteasomal inhibition enhanced the expression of endodermal genes while increasing the proteasomal activity hindered definitive endodermal differentiation. Proteasomal inhibition at the definitive endodermal stage culminated in an enriched generation of insulin-positive cells. Elevated endodermal gene expression was consistent in mESCs and hIPSCs upon proteasomal inhibition. Mechanistic insight revealed the proteasome-inhibited enhanced endodermal differentiation to be via modulating the YAP pathway.SIGNIFICANCEOur study unravels the specific involvement of UPS in endoderm cell generation from pluripotent stem cells and paves the way for obtaining potential definitive endodermal cells for plausible cellular therapy in the future.

01 Dec 2024·Molecular Biology Reports

Epigenetic-related transcriptional reprogramming elucidated by identification and validation of a novel reference gene combination for RT-qPCR studies in porcine oocytes of contrasting quality

Article

Author: Haug, Linda Marijke ; Alm-Kristiansen, Anne Hege ; Wilson, Robert C

AbstractBackgroundReliable RT-qPCR results are dependent on appropriate normalisation. Oocyte maturation studies can be challenging in this respect, as the stage of development can distinctively affect reference gene transcript abundance. The aim of this study was to validate the use of reference genes in oocyte in vitro maturation RT-qPCR studies, and thereafter, examine the abundance of transcripts supporting histone modification during oocyte and early embryo development in oocytes of contrasting quality.Methods and resultsTotal RNA from oocytes from prepubertal gilts and sows was extracted either directly succeeding follicle aspiration or after 44 h in vitro maturation, followed by RT-qPCR. The stability of YWHAG, HPRT1, ACTB, GAPDH, HMBS and PFKP, was analysed by NormFinder and further cross-validated by assessing results generated following application of different combinations of potential reference genes for normalisation of the RT-qPCR data. Combining ACTB and PFKP generated high stability according to NormFinder and concordant results. Applying this normalisation, gilt derived oocytes displayed significantly higher abundance than oocytes from sows of almost all the epigenetic-related transcripts studied (HDAC2, SIRT1, SALL4, KDM1A, KDM1B, KDM5A), both before and after maturation.ConclusionsThis study identified the combined use of ACTB and PFKP as the optimal normalisation for porcine oocyte RT-qPCR data. In oocytes collected from prepubertal gilts, transcription did not appear to be silenced at the time of aspiration, and accumulation of transcripts supporting histone modification facilitating proper fertilization and further embryo development seemed delayed. The results imply the epigenetic-related transcripts may have potential as markers of oocyte quality.

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