ulodesine (BCX4208) / BioCryst - LARVOL DELTA

A Novel Heterobifunctional ALOX15 Degrader for Treatment of Nasal Polyps (ATS 2025) - "A Genome Wide Association Study (GWAS) reported a loss of function missense variant in ALOX15 (rs34210653, Thr560Met, minor allele frequency = 3%) demonstrated protection against nasal polyps (68%), rhinosinusitis (36%), and hay fever (19%)...Human ALOX15 knock-in mice (mouse Alox15 replaced with human ALOX15) were created to demonstrate in vivo efficacy of compound A due to lack of cross-reactivity to mAlox15 (ortholog only shares 74% amino acid identity with hALOX15). Conformation of in vivo activity of compound A was demonstrated in healthy knock-in mice as a 54% decrease in ALOX15 expression and decreased nuclear Ki-67 staining in femur bone marrow cells after 4 daily intraperitoneal doses of 100 mg/kg of compound A. These data suggest that compound A is a potent and selective degrader that can effectively reduce ALOX15 in vivo with potential for the treatment of nasal polyps."

Allergic Rhinitis • Immunology • Nasal Polyps • Otorhinolaryngology • Respiratory Diseases • Sinusitis • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • ALOX15 • IL4

Metabolic constraint of human telomere length by nucleotide salvage efficiency. (PubMed, Nat Commun) - "Circumventing limits on salvage by expressing Drosophila melanogaster deoxynucleoside kinase or augmenting dG metabolism using the PNP inhibitor ulodesine robustly lengthened telomeres in human cells, including those from patients with lethal telomere diseases. Our results provide an updated paradigm for telomere length control, wherein telomerase reverse transcriptase activity is actively and bidirectionally constrained by the availability of its dNTP substrates, in a manner that may be therapeutically actionable."

Journal • DCK • TERT

Perspectives and challenges in developing small molecules targeting purine nucleoside phosphorylase. (PubMed, Eur J Med Chem) - "However, only Peldesine, Forodesine and Ulodesine have entered clinical trials and exhibited some potential for the treatment of T-cell leukemia and gout. The most recent direction in PNP inhibitor development has been focused on PNP small-molecule inhibitors with better potency, selectivity, and pharmacokinetic property. In this perspective, considering the structure, biological functions, and disease relevance of PNP, we highlight the recent research progress in PNP small-molecule inhibitor development and discuss prospective strategies for designing additional PNP therapeutic agents."

Journal • Review • Developmental Disorders • Gout • Hematological Malignancies • Immunology • Inflammatory Arthritis • Leukemia • Lymphoma • Oncology • Rheumatology

NME1 and DCC variants are associated with susceptibility and tumor characteristics in Mexican patients with colorectal cancer. (PubMed, J Egypt Natl Canc Inst) - "These findings suggest that the NME1 rs34214448 and DCC rs2229080 variants play a significant role in colorectal cancer development."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • DCC • NTN1

Chromosome 10q24.32 Variants Associate With Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study. (PubMed, J Am Heart Assoc) - "The current study reveals 3 novel risk loci (CNNM2, NT5C2, and AS3MT) associated with BADs. These findings may help elucidate the mechanism by which BADs may influence cerebrovascular health."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Vascular Neurology • NT5C2

A polygenic risk score for predicting racial and genetic susceptibility to prurigo nodularis. (PubMed, J Invest Dermatol) - "We also perform genome-wide association (GWA) analyses which uncover genetic variants associated with PN, including one near PLCB4 (rs6039266: OR 3.15, P = 4.8 × 10) and others near TXNRD1 (rs34217906: OR 1.71, P = 6.4 × 10; rs7134193: OR 1.57, P = 1.1 × 10)...Strikingly, this association was more significant with race than after adjusting for genetic ancestry. As race is a sociocultural construct and not a genetically bound category, our findings suggest that genetics, environment influence, and social determinants of healthy likely affect the development of PN and may contribute to clinically observed racial disparities."

Journal • Dermatology • Immunology • Inflammation • Prurigo Nodularis • Pruritus • PLCB4

Variant Load in Childhood Nephrotic Syndrome Is Associated With Pattern of Therapy Response (KIDNEY WEEK 2022) - "Genotyping was done using TaqMan and Direct Sanger Sequencing for 10 childhood NS risk loci: HLA-DQA1 (rs1129740 & rs1071630), BTNL2 (rs9348883), HLA-DR/DQ (rs4642516 & rs3134996), Intergenic (rs9273371), CALHM6 (rs2637678), NPHS1/KIRREL (rs56117924), TNFSF15 (rs6478109), and TNFRSF11A (rs34213471)...Variant load was associated with both SRNS and FR/SD (SRNS vs. SSNS p=1.98e -15 and IFR vs. FR/SD p=0.002). Conclusion Our study showed that genetic risk loci for childhood NS are associated with pattern of therapy response and may predict disease outcome."

Clinical • Glomerulonephritis • Nephrology • Pediatrics • Renal Disease • CD40LG • HLA-DQA1 • NPHS1 • TNFRSF11A

[VIRTUAL] EXPANDED GENOME-WIDE ASSOCIATION STUDY OF IBD IDENTIFIES OVER 80 NOVEL LOCI AND IMPLICATES NEW GENES AND PATHWAYS IN DISEASE SUSCEPTIBILITY (DDW 2021) - "DOK2 (rs34215892 NP_003965:p.P274L; OR = 1.23 p = 4.0x10-10) is a cytoplasmic signalling protein that is highly expressed in macrophages and T cells in the terminal ileum... We identified 81 novel genome-wide significant (p<5x10-8) IBD loci, ten of them driven by variants with low minor allele frequency (MAF <0.01) (Figure 1). Five of the associated regions contain genes implicated in monogenic autosomal recessive syndromes that include colitis: DOCK8, G6PC3, HPS4, NCF1, RAG1, and RAG2. Many risk loci causally alter the expression of nearby genes, suggesting that aberrant expression of these genes underpins the IBD association, including TNFRSF8, PLCG1-AS1, ITPKC and CSF1."

Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Primary Immunodeficiency • Targeted Protein Degradation • Ulcerative Colitis • CSF1 • IL17A • IL22 • TNFRSF8

A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival. (PubMed, NPJ Precis Oncol) - "We identified two SNPs, rs34211819 at 7p12.3 (P = 3.90 × 10) and rs1143149 at 7p14.2 (P = 9.75 × 10), were significantly associated with survival of NSCLC patients who were long-term former smokers...Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Tobacco Cessation • TNS3

Inosine induces acute hyperuricaemia in rhesus monkey (Macaca mulatta) as a potential disease animal model. (PubMed, Pharm Biol) - "Ulodesine, allopurinol and febuxostat eliminated the inosine-induced elevation in SUA in tested monkeys. An acute HUA animal model with high reproducibility was induced; it can be applied to evaluate new anti-HUA drugs in vivo and explore the disease pathogenesis."

Journal • Preclinical • ABCG2

Genome-wide characterization of the cellulose synthase gene superfamily in Pyrus bretschneideri and reveal its potential role in stone cell formation. (PubMed, Funct Integr Genomics) - "Furthermore, the expression levels of four genes (Pbr032894.2, Pbr016107.1, Pbr00518.1, and Pbr034218.1) tended to first increase and then decrease during fruit development, implying that these four genes may be involved in the development of stone cells of pear fruit. Our results may help elucidate the evolutionary history and functional differences of the CesA/Csl genes in pear and lay a foundation for further investigation of the CesA/Csl genes in pear and other Rosaceae species."

Journal • Dermatology • Dermatopathology

Integrase strand transfer inhibitors and neuropsychiatric adverse events in a large prospective cohort. (PubMed, J Antimicrob Chemother) - "INSTIs were prescribed to 21315 patients: 6274 received dolutegravir, 3421 received elvitegravir boosted by cobicistat, and 11620 received raltegravir...The association with abacavir was not retained in the final model. Although discontinuation for side effects was less frequent with dolutegravir than with boosted elvitegravir, discontinuation for NPAEs, although rare (2.7%), was more frequent with dolutegravir. No patient characteristic was found to be associated with these side effects in this very large population."

Adverse events • Clinical • Journal • Infectious Disease

The effectiveness of oral Phloroglucin as premedication for non‐sedative esophagogastroduodenoscopy: A double‐blinded, placebo‐controlled, randomized controlled trial (APDW 2018) - "Oral Phloroglucin (Flospan®) significantly suppress gastrointestinal peristalsis during non-sedative EGD compared with placebo. (Clinical trial registration number: NCR03342118)"

Clinical • Biosimilar