Lunaphen (4 Phenyl butyrate prolonged-release) / Lunamed Operations - LARVOL DELTA

4-Phenylbutyrate Restores GABAergic Synaptic Dysfunction in Slc6a1+/S295L and Gabrg2+/Q390X Mouse Models of Genetic Epilepsy (AES 2025) - "In recent years, we found that chemical chaperone 4-phenyl butyrate (4-PBA) treatment mitigated seizures and addressed multiple aspects of underlying pathology in two monogenetic GEs with mutations in vital constituents of GABAergic neurotransmission: 1) developmental and epileptic encephalopathy associated with S295L mutation in SLC6A1, encoding GABA transporter 1, and 2) Dravet syndrome associated with Q390X mutation in GABRG2, encoding ɣ2 subunit of the GABAA receptor.We hypothesize that 4-PBA acts in a targeted fashion to reverse GABAergic dysfunction in these disorders, making it an excellent candidate for novel precision therapy that is applicable to multiple GEs... Prolongation of synaptic currents in Slc6a1+/S295L mice is consistent with role of GAT-1 as the primary mechanism of uptake of extrasynaptic GABA after its release. Previously, we reported that 7-day PBA treatment leads to a significant reduction of seizures; we did not observe a matching restoration of..."

Preclinical • CNS Disorders • Epilepsy • Gene Therapies

Heterozygous Missense Variants in the ATPase Phospholipid Transporting 9A Gene, ATP9A, Alter Dendritic Spine Maturation and Cause Dominantly Inherited Nonsyndromic Intellectual Disability. (PubMed, Hum Mutat) - "In a patient with a similar phenotype, we also identified two truncating variants in ATP9A (p.(Arg145⁣∗), p.(Glu901⁣∗)), adding a novel family to the six already described in the literature with the recessive mode of inheritance...Our results therefore demonstrate the pathogenicity of ATP9A heterozygous missense variants and confirm the role of ATP9A in neuronal maturation and in brain wiring during development. They strengthen the association of ATP9A with neurodevelopmental disorders and demonstrate that a double mode of inheritance should be considered for ATP9A-related disorders."

Journal • CNS Disorders • Developmental Disorders • Mental Retardation • Psychiatry

Developing Topics. (PubMed, Alzheimers Dement) - "Our data suggest that relieving proteostatic stress with chemical chaperones mitigates the effects of CSS on learning and memory."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Metabolic Disorders • Sleep Disorder

Chemical chaperones mitigate chronic short sleep induced cognitive impairment (AAIC 2024) - " 2-month-old male and female C57BL/6 mice underwent 4 weeks of CSS for 8hrs/day; 3 days/week by exposure to an enriched environment with or without 4-phenyl butyrate (PBA) treatment... Our data suggest that relieving proteostatic stress with chemical chaperones mitigates the effects of CSS on learning and memory."

Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Metabolic Disorders • Sleep Disorder

Pharmacological inhibition of endoplasmic reticulum stress mitigates osteoporosis in a mouse model of hindlimb suspension. (PubMed, Sci Rep) - "We investigated the effects of inhibiting endoplasmic reticulum (ER) stress with 4-phenyl butyrate (4-PBA) on the morphology, physicochemical properties, and bone turnover markers of hindlimbs in HLS mice...Treatment with 4-PBA partially restored normal bone histology, increased collagen crosslinking, and mineralization, promoted anti-inflammatory markers, and downregulated bone resorption markers. Our findings suggest that mitigating ER stress with 4-PBA could be a therapeutic intervention to offset osteoporosis in conditions mimicking hindlimb suspension."

Journal • Preclinical • Osteoporosis • Rheumatology • CTSK

4-PBA exerts brain-protective effects against sepsis-associated encephalopathy in a mouse model of sepsis. (PubMed, Exp Neurol) - "Our results suggest that administration of 4-PBA treatment significantly attenuates ERS, alleviates cognitive decline, reduces inflammatory damage, and restores mitochondrial dynamics via the IRE1α/Xbp1s-Ca2+-associated pathway, which provides a new potential therapeutic approach to SAE."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Infectious Disease • Inflammation • Septic Shock

Chaperone interventional therapy restores proteostasis, improves cognition and increases ADAM10 in young and aged APP knockin mice (AAIC 2023) - "Two groups of mice and their wildtype littermates, (treatment starting early at 1-2 mos old and late at 12 mos old) were administered the chemical chaperone 4-phenyl butyrate (PBA) by weekly I.P. for 10 weeks... Reducing proteostatic stress even at a late age improves cognition in a mouse model of Alzheimer’s disease. The implications of these results could have an impact on the development of therapies to inform the development of potential treatments for Alzheimer’s disease."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • ADAM10 • HSPA5

Bozitinib, a highly selective inhibitor of cMet, demonstrates robust activity in gastric, lung, hepatic and pancreatic in vivo models (AACR 2017) - P1; "...In particular, in the LU1901 model, bozitinib (BT) was compared to capmatinib (INC280)... In MKN45, LU2503, LIM0612 and LIM0801, the effect of BT seemed superior than that of crizotinib; in LUM858, its effect was higher than that of erlotinib; in LU1901, its effect was higher than that of crizotinib and INC280... In conclusion, BT was well-tolerated, with no animal death nor major weight loss. The in vivo experiments demonstrated that BT is a viable candidate with effective anti-tumor activities. BT is currently under evaluation in cMet dysregulated NSCLC (NCT02896231) with additional trials planned."

Biosimilar • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Design and synthesis of lanthanide phosphate coordination polymers (ACS-Sp 2023) - "(2) and (4) synthesized both PCL and poly gamma-functionalized CL with various linkages at the gamma position, including benzyl, 4-phenyl butyrate, acetate, and bromo with PDI=1.22-1.84. Based on kinetic studies and synthesized block copolymers like poly (β-myrcene)-b-poly (isoprene) and poly (β-myrcene)-b-PMMA, all our catalytic systems demonstrated the quasi-living behavior.R = TEP (triethyl phosphate), TIBP (triisobutylphosphate), and TEHP (tris(2-ethylhexyl) phosphate)Z = Benzyl, 4-Phenyl butyrate, Acetate, Bromo, gamma-2-[2-(2-methoxyethoxy)ethoxy]ethoxy"

Reducing ER stress with chaperone therapy reverses sleep fragmentation and cognitive decline in aged mice. (PubMed, Aging Cell) - "We administered the chemical chaperone 4-phenyl butyrate (PBA) to aged and young mice, and monitored sleep and cognitive behavior...Together, these results indicate that restoring proteostasis improves sleep and cognition in a wild-type mouse model of aging. The implications of these results could have an impact on the development of therapies to improve health span across the aging population."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Sleep Disorder • HSPA5

Analysis of ALMS1 gene variants in seven patients with Alström syndrome (PubMed, Zhonghua Yi Xue Yi Chuan Xue Za Zhi) - "ALMS1 variants probably underlay the Alström syndrome in the 7 patients, and genetic testing can provide a basis for the clinical diagnosis of this syndrome. The discovery of four novel variants has expanded the mutational spectrum of Alström syndrome."

Clinical • Journal • Alstrom Syndrome

Modifying gap junction communication in cancer therapy. (PubMed, Curr Res Transl Med) - "An enhancement of GJIC function by HDACi and ATRA increased cytotoxicity and could be effective in the presence of Dexamethasone, when combined with ATRA or VPA."

Journal • Oncology • CDH1 • GAPDH • GJA1

Urinary ERdj3 and mesencephalic astrocyte-derived neutrophic factor identify endoplasmic reticulum stress in glomerular disease. (PubMed, Lab Invest) - "Rats with PHN were treated with the chemical chaperone, 4-phenyl butyrate (PBA), starting at the time of disease induction, or after disease was established...In conclusion, urinary ERdj3 and MANF reflect glomerular ER stress. 4-PBA protected against complement-mediated podocyte injury and the therapeutic response could be monitored by urinary ERdj3 and MANF."

Journal • CNS Disorders • Glomerulonephritis • Immunology • Lupus Nephritis • Nephrology • Renal Disease

[VIRTUAL] A role for cellular stress in age-related sleep impairments and cognitive decline (ESRS 2020) - "old) were administered the chemical chaperone 4-phenyl butyrate (PBA) by weekly injections and in the drinking water... These results suggest that reducing cellular stress improves cognition in a wildtype mouse model of aging. While sleep and histological data analyses are still in progress, the implications of these results could have an impact on the development of therapies to improve healthspan in the growing aged population."

Alzheimer's Disease • Cognitive Disorders

A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin. (PubMed, Int J Mol Sci) - "A short-chain fatty acid, 4-Phenyl butyrate (4-PBA), is an acid chemical chaperone that acts as a histone deacetylase inhibitor (HDACi) to promote chromosomal histone acetylation...Moreover, 4-PBA also disrupted the integrity of the membranous web and interfered with the molecular interactions critical for the assembly of the HCV replication complex. These findings suggest that 4-PBA is a key epigenetic inducer of anti-HCV hepatic hepcidin and might at least in part play a role in targeting host factors related to HCV infection as an attractive complement to current HCV therapies."

Journal • Hepatitis C Virus • Infectious Disease

Perfluorooctanoic acid activates the unfolded protein response in pancreatic acinar cells. (PubMed, J Biochem Mol Toxicol) - "PFOA-stimulated activation of the UPR was blocked by pretreatment with specific PERK and IRE1α inhibitors and the chemical chaperone 4-phenyl butyrate, but not the antioxidants N-acetyl- l-cysteine and Tiron. PFOA treatment led to increased cytosolic Ca levels and induction of the UPR was blocked by an inhibitor of the inositol 1,4,5-trisphosphate receptor. These findings indicate that PFOA-induced ER stress may be the mechanistic trigger leading to oxidative stress in the pancreas."

Journal • PERK

Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus. (PubMed) - J Mol Endocrinol - "The administration of 4-phenyl butyrate (PBA), a chemical chaperone of protein folding and UPR activator, in the offspring from postnatal day 4 significantly reduced their body weight, fat deposition, which were in association with increased Activating transcription factor (ATF)4, immunoglobin-binding protein (BiP) and Erdj4 mRNA as well as reduced Parkin, PTEN-induced putative kinase (PINK)1 and Dynamin-related protein (Drp)1 protein expression levels. These results suggest that hypothalamic ER stress and mitophagy are among the regulatory factors of offspring metabolic changes due to maternal obesity."

Journal • Biosimilar • Obesity

Interplay between Endoplasmic Reticulum (ER) Stress and Autophagy Induces Mutant p53H273 Degradation. (PubMed, Biomolecules) - "ER stress inhibition with chemical chaperone 4-phenyl butyrate (PBA) impaired mutp53 downregulation, which is similar to IRE1α/XBPI specific inhibition, reducing cancer cell death...Recently discovered small molecules targeting components of the UPR show promise as a novel anticancer therapeutic intervention. However, our findings showing UPR activation during mutp53 degradation indicate that caution is necessary in the design of therapies that inhibit UPR components."

Journal • TP53

"Hi @SEngelborghs @J_C_MD_PhD @sanchezvaller @jmschott @cathmummery @jineto_ARL @PhilipAlz @JFDemonet @MerceBoadaR @FundacioACE @iCABNetwork @SantPauMemory @LuLu99015906 @jakub_hort welcome to a new 3 year cycle of #EADC & growing our research together! More to follow!!!" (@ProfPatKehoe)