AMPA regulation is feather in proteasome’s cap
Researchers have discovered that a subunit of the ubiquitin-proteasome system acted independently of the proteasome machinery to regulate AMPA receptors, a type of glutamate receptor, at multiple steps of their life cycle. Published in the May 26, 2023, issue of Science, the findings could point to ways to target AMPA receptors. They are responsible for the majority of excitatory transmission in the central nervous system, and current drugs seeking to influence AMPA-based transmission are “good but they are not great,” Erin Schuman told BioWorld. “This regulatory particle is watching the glutamate receptor at each step.” Schuman is the director of the Max Planck Institute for Brain Research and the paper’s senior author.

AMPA regulation is feather in proteasome’s cap
Researchers have discovered that a subunit of the ubiquitin-proteasome system acted independently of the proteasome machinery to regulate AMPA receptors, a type of glutamate receptor, at multiple steps of their life cycle. Published in the May 26, 2023, issue of Science, the findings could point to ways to target AMPA receptors. They are responsible for the majority of excitatory transmission in the central nervous system, and current drugs seeking to influence AMPA-based transmission are “good but they are not great,” Erin Schuman told BioWorld. “This regulatory particle is watching the glutamate receptor at each step.” Schuman is the director of the Max Planck Institute for Brain Research and the paper’s senior author.
Mdm4 inhibitor XI-011 reduces lung fibrosis in IPF model
Idiopathic pulmonary fibrosis (IPF) is a rare, progressive and chronic lung disease that causes scarring of the lung tissue and leads to an irreversible decline in lung function. Several studies have linked the p53 tumor suppressor gene to pulmonary fibrosis.
TAVT-135 increases intracellular chloride ion transport and airway hydration in vitro
At the recent ATS meeting, Tavanta Therapeutics Inc. introduced TAVT-135, a cell-penetrating peptide (CPP) conjugate that acts as a chloride ion (Cl-) transporter. The product is currently being investigated for cystic fibrosis (CF), regardless of CF transmembrane conductance regulatory (CFTR) gene mutation status.
Other news to note for May 30, 2023
Additional early-stage research and drug discovery news in brief.
Hilleman Laboratories and A*STAR collaborate to develop circRNA vaccine for Nipah virus
Hilleman Laboratories Singapore Pte Ltd. and the Agency for Science, Technology and Research (A*STAR) have established a collaboration to explore using novel circular ribonucleic acid (circRNA) technology to develop a Nipah virus vaccine and to validate the technology platform for application for other infectious diseases pathogens.
Sanford-Burnham Medical Research Institute patents new BIRC7 inhibitors
Sanford-Burnham Medical Research Institute has disclosed baculoviral IAP repeat-containing protein 7 (BIRC7; ML-IAP) inhibitors reported to be useful for the treatment of cancer.
TRAIL combination therapy with TR-107 shows promise in glioblastoma multiforme
Glioblastoma multiforme (GBM) is an aggressive brain cancer with poor prognosis and survival. TNF-related apoptosis-inducing ligand (TRAIL) is a protein that induces apoptosis in cancer cells by binding death receptors type 4 and 5. Researchers at the University of North Carolina explored using hiNeuroS-TRAIL combined with the ClpP activator TR-107 as a potential treatment.

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Conferences

Preliminary results for NEU1-expressing gene therapy in preclinical sialidosis
Endocrine/Metabolic
Sialidosis is a lysosomal storage disease caused by mutations in the NEU1 gene, which encodes sialidase neuraminidase 1. These mutations lead to enzyme deficiency and subsequently accumulation of oligosaccharides and sialylated glycopeptides in tissues and body fluids, which in turn lead to cell...
Optimized mesenchymal stem cell therapy exhibits efficacy in preclinical model of pulmonary hemorrhage
Immune
The targeted delivery of optimized stem cells directly into injured tissues has been used to maximize efficacy and minimize systemic exposure. Still, despite hundreds of clinical trials evaluating mesenchymal stem cell (MSC) therapy as a treatment, clinical efficacy remains highly variable....
NGGT-002 gene therapy shows potential for treating phenylketonuria
Endocrine/Metabolic
NGGT (Suzhou) Biotechnology Co. Ltd. has presented preclinical data on an AAV vector approach that expresses human PAH, rAAV8-PAH, also known as NGGT-002. NGGT-002 has liver tropism and it was codon-optimized for expressing PAH in the liver.
HLCN-061 demonstrates enhanced persistence, migration and cytotoxicity in preclinical models
Cancer
Researchers from Healios K.K. presented preclinical data for HLCN-061, a novel gene-engineered human induced pluripotent stem cell (iPSC)-derived NK cell product being developed for the treatment of solid tumors.

Cancer

SMARCB1 degradation protects renal cells from hypoxic stress
Renal medullary carcinoma (RMC) is characterized by the complete loss of the SMARCB1 tumor suppressor, and it predominantly affects individuals with sickle cell trait (SCT), characterized by increased sickling of red blood cells in the renal medulla. It has been previously demonstrated that RMC...

Infection

Studying bacterial ‘trash’ can rapidly detect response to antibiotics
By sequencing the bacterial mRNA that bacteria break down (the degradome) during protein synthesis, a novel approach called 5PSeq was able to analyze how environmental exposure stress, including that of antibiotics, affected bacterial translational dynamics. This is what researchers from the...

Roche prepares and tests new LpxH inhibitors for the treatment of bacterial infections
Patents
F. Hoffmann-La Roche Ltd. and Hoffmann-La Roche Inc. have identified piperazinylsulfonylaryl compounds acting as UDP-2,3-diacylglucosamine hydrolase (LpxH) (bacterial) inhibitors.
AAV9-based therapy neutralizes rabies viral infection in neurons
Conferences
Rabies virus is among the most neurotrophic known virus and it has a fatality rate of almost 100%. There is a need for antibody-induced protection in the central nervous system, since rabies virus can cross the blood-brain barrier but antibodies cannot. Investigators from Auburn University and the...

Neurology/Psychiatric

Amplo’s AAV-ColQ gene therapy AMP-201 receives fast track STTR funding
Gene therapy
Amplo Biotechnology Inc. has been awarded a fast track phase I/II Small Business Technology Transfer (STTR) grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) to fund further development of AMP-201, an AAV-ColQ...
Researchers create new mouse model of DMD using knock-in of human exon 50
Conferences
Researchers from HuidaGene Therapeutics Co. Ltd. have evaluated the effects of adenine base editing (ABE)-induced exon skipping of exon 50 in a humanized mouse model of Duchenne muscular dystrophy (DMD).
AAV9-CLN5 improves symptoms in mice with Batten disease
Conferences
Neuronal ceroid lipofuscinosis, commonly known as Batten disease, is an inherited pediatric neurodegenerative lysosomal storage disease caused by mutations in the CLN5 gene. The disease is incurable and there is an urgent medical need for novel therapies. A murine model of Batten disease was...
MyoDys45-55 restores dystrophin and improves functional measures in murine model of DMD
Genetic/Congenital
Myogene Bio LLC has developed an approach through CRISPR7Cas9 technology...
Psilera nominates non-hallucinogenic psilocybin derivative as lead clinical candidate
Substance use and poisoning
Psilera Inc. has selected a novel, non-hallucinogenic psilocybin derivative, PSIL-006...

Endocrine/Metabolic

AAV9-GLA restores α-galactosidase levels in murine model of Fabry disease
Conferences
Fabry disease is a metabolic disease characterized by a deficiency in the lysosomal α-galactosidase enzyme caused by mutations in the GLA gene. This leads to substrate accumulation in the lysosomes, cellular dysfunction and organ damage.

Biomarkers

Low miR-143 expression and high MSI2 expression are associated with poor prognosis in AML
Cancer
Researchers from Wenzhou Medical University and affiliated organizations have published data from a study that aimed to investigate the relationship between the tumor suppressor microRNA-143 (miR-143) and RNA-binding protein Musashi homolog 2 (MSI2), the abnormal expression of which has been...

SDC4 confers poor survival in gastric cancer
Cancer
Gastric cancer persists as the fourth leading cause of cancer-related deaths. Syndecans (SDCs) are a family of four transmembrane heparan sulfate proteoglycans involved in cell proliferation, migration and adhesion, among others, and syndecan-4 (SDC4) expression has been shown to be up-regulated...
SNP in miR-146a is a prognostic marker in acute coronary syndrome
Cardiovascular
Despite advances in diagnosis and treatment, cardiovascular disease remains the leading cause of death worldwide. Single-nucleotide polymorphisms (SNPs) in microRNAs are known to play important roles in acute coronary syndrome (ACS). MicroRNA 146a (miR-146a) is significantly upregulated in human...

Gastrointestinal

NTX-1175 channel blocker is effective in visceral pain models
Conferences
Patients with irritable bowel syndrome (IBS) have chronic abdominal pain as a result of visceral hypersensitivity. Voltage-gated sodium channels control cellular excitability and are involved in the pathophysiology of several functional...
Small-molecule AXIN stabilizer from University of Maryland inhibits liver fibrosis
Conferences
Researchers from the University of Maryland presented preclinical data for YA-6060, a novel small molecule showing dual activities of Wnt inhibition and AMPK activation via the mechanism of AXIN stabilization. Since both Wnt/β-catenin and AMPK...
Insilico Medicine identifies new PHD2 inhibitors
Patents
An Insilico Medicine IP Ltd. patent describes Egl nine homolog 1 (EGLN1; HPH-2; PHD2) inhibitors reported to be useful for the treatment of ulcerative colitis and Crohn’s disease.
LPA1 receptor agonist improves NASH-related outcomes in preclinical models
Conferences
Currently, there is no FDA-approved drug for nonalcoholic steatohepatitis (NASH), which has evolved into the second leading cause of liver transplantation in the U.S. Researchers from Children’s Hospital Los Angeles and Epigen Biosciences Inc....
Researchers present data from murine studies of PAM-369, a muscarinic M3 receptor PAM for enteropathy
Conferences
Researchers from Kyushu University and Mochida Pharmaceuticals Co. Ltd. disclosed recent data along with the chemical structure of PAM-369, a novel muscarinic acetylcholine M3 receptor positive allosteric modulator (PAM), being developed for the...
Researchers report discovery of ROR-107, a GPBAR1 agonist and RORγt inverse agonist for IBD
Conferences
Inflammatory bowel disease (IBD) is a chronic, immunologically mediated disorder of the gastrointestinal tract in which tissue damage and sustained inflammation lead to long-term dysfunction of the gastrointestinal tract.

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