PF-655 / SBI Biotech - LARVOL DELTA

Spike RBD drives sustained Parkinson's disease progression via microglia-neuron crosstalk-mediated RTP801 upregulation. (PubMed, J Adv Res) - "Our findings demonstrate that SARS-CoV-2 RBD exacerbates PD progression through a pathogenic crosstalk between microglia and neurons. This neurotoxic signaling is mediated by a mitochondrial mtDNA-cGAS-STING-IFNβ/RTP801 axis. Targeting RTP801 or the STING pathway may therefore represent a promising therapeutic strategy to mitigate long COVID-associated progression of PD."

Journal • CNS Disorders • Infectious Disease • Metabolic Disorders • Movement Disorders • Novel Coronavirus Disease • Parkinson's Disease • Psychiatry • Respiratory Diseases • CXCL8 • DDIT4 • IFNB1 • IL6

Nrf2- and p53-inducible REDD2/DDiT4L/Rtp801L confers pancreatic β-cell dysfunction, leading to glucose intolerance in high-fat diet-fed mice. (PubMed, J Biol Chem) - "In both STZ-induced male and female and HFD-fed male models, β-cell specific Redd2-knockout improved glucose tolerance without affecting insulin sensitivity. Our results identify REDD2 as a novel regulator of β-cell dysfunction under oxidative stress."

Journal • Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • NFE2L2

Astrocytes, via RTP801, contribute to cognitive decline by disrupting GABAergic-regulated connectivity and driving neuroinflammation in an Alzheimer's disease mouse model. (PubMed, Alzheimers Dement) - "The 5xFAD mouse model of Alzheimer's disease presents higher levels of RTP801 in hippocampal astrocytes. Normalizing the levels of astrocytic RTP801 prevents cognitive decline and restores anxiety-like behavior in the 5xFAD mouse model. Knocking down astrocytic RTP801 preserves the resting-state functional connectivity in the 5xFAD mouse model. Astrocytic RTP801 mediates the loss of Parvalbumin+ interneurons, negatively affecting the levels of γ-aminobutyric acid (GABA) in the 5xFAD mouse model. Astrocytic RTP801 contributes to astro- and microgliosis and inflammasome expression in the 5xFAD mouse model."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • Mood Disorders • Psychiatry • DDIT4

Lower cytoplasmic expression of DDIT4 is associated with poor prognosis in gastric cancer patients. (PubMed, Discov Oncol) - "Lower cytoplasmic expression of DDIT4 could serve as a promising prognostic biomarker in GC."

Journal • Gastric Cancer • Oncology • Solid Tumor • DDIT4

Deletion of the stress response protein REDD1 prevents sodium iodate-induced RPE damage and photoreceptor loss. (PubMed, Geroscience) - "Overall, REDD1 deletion was sufficient to prevent retinal oxidative stress, RPE damage, immune cell activation, and photoreceptor loss in response to NaIO3. The findings support a potential role for REDD1 in the development of retinal complications in the context of dry AMD."

Journal • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders

RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease. (PubMed, Nucleic Acids Res) - "Finally, the tRNA-enriched fraction obtained from 5xFAD mice promoted abnormal dendritic arborization in cultured hippocampal neurons, and RTP801 silencing in the source neurons prevented this phenotype. Altogether, these results show that elevated RTP801 impairs RNA processing in vitro and in vivo in the context of AD and suggest that RTP801 inhibition could be a promising therapeutic approach."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • DDIT4 • DDX1 • XBP1

Ginsenoside Rg1 ameliorates stress-exacerbated Parkinson's disease in mice by eliminating RTP801 and α-synuclein autophagic degradation obstacle. (PubMed, Acta Pharmacol Sin) - "Moreover, Rg1 alleviated obstacles in αSyn autophagic degradation by ameliorating the RTP801-TXNIP-mediated deficiency of ATP13A2. Collectively, our results suggest that ginsenoside Rg1 holds promise as a therapeutic choice for treating PD-sensitive individuals who especially experience high levels of stress and self-imposed expectations."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • Targeted Protein Degradation • DDIT4 • TXNIP

REDD1 Deletion Suppresses NF-κB Signaling in Cardiomyocytes and Prevents Deficits in Cardiac Function in Diabetic Mice. (PubMed, Int J Mol Sci) - "By contrast, REDD1-/- mice did not exhibit a diabetes-induced deficit in ejection fraction and left ventricular chamber dilatation was reduced in diabetic REDD1-/- mice, as compared to diabetic REDD1+/+ mice. Overall, the results support a role for REDD1 in promoting GSK3β-dependent NF-κB signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice."

Journal • Preclinical • Cardiomyopathy • Cardiovascular • Diabetes • Heart Failure • Inflammation • Metabolic Disorders • CCL2 • IL1B • TNFA

REDD1 redox modification acts as a molecular sensor in retinal disease (ARVO 2024) - "Purpose: We previously demonstrated that an increased abundance of the stress response protein Regulated in Development and DNA damage 1 (REDD1, also known as RTP801/DDIT4) in the retina contributes to the development of retinal pathology and impaired visual function in mice... The results reveal a new molecular redox switch in the REDD1 protein that is activated in the context of retinal disease. Genetic or small molecule inhibition of REDD1 protein allostery may represent a new clinically translatable therapeutic intervention. Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand."

Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Ophthalmology • Retinal Disorders • DDIT4

RTP801 mediates transneuronal toxicity in culture via extracellular vesicles. (PubMed, J Extracell Vesicles) - "Interestingly, EVs derived from neurons where RTP801 was silenced prior to exposing them to 6-OHDA maintained Akt and RPS6 transactivation in recipient neurons. Taken together, these results suggest that RTP801-induced toxicity is transferred via EVs, and therefore, it could contribute to the progression of neurodegenerative diseases, in which RTP801 is involved."

Journal • CNS Disorders • DDIT4 • RPS6

REDD1-dependent GSK3β dephosphorylation promotes NF-κB activation and macrophage infiltration in the retina of diabetic mice. (PubMed, J Biol Chem) - "In contrast with STZ-diabetic mice receiving a vehicle control, macrophage infiltration was not observed in the retina of STZ-diabetic mice treated with GSK3 inhibitor. Collectively, the findings support a model wherein diabetes enhances REDD1-dependent activation of GSK3β to promote canonical NF-κB signaling and the development of retinal inflammation."

Journal • Preclinical • Diabetes • Diabetic Retinopathy • Inflammation • Metabolic Disorders • Ocular Inflammation • Retinal Disorders • GSK3B

CHOP promotes coelomocyte apoptosis through p38-MAPK pathway in Vibrio splendidus-challenged sea cucumber Apostichopus japonicus. (PubMed, Fish Shellfish Immunol) - "The deuced amino acid of AjCHOP shared a conserved RTP801_C domain from 63 to 171 aa...Mechanically, AjCHOP-mediated apoptosis was dependent on the activation of p38-MAPK pathway but not JNK/ERK-MAPK. Overall, our results supported that V. splendidus triggers apoptosis among the coelomocytes, whereas AjCHOP mediates through the p38-MAPK pathway in A. japonicus."

Journal

RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington's Disease. (PubMed, Biomolecules) - "This recovery is associated with a partial rescue of synaptic markers and with a reduction in inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Huntington's Disease • Immunology • Inflammation • Movement Disorders • Parkinson's Disease • DDIT4

Hypoxia-responsive expression of vascular endothelial growth factor for induction of angiogenesis in artificial three-dimensional tissues. (PubMed, J Biosci Bioeng) - "The genetically modified cell sheet was subcutaneously transplanted into mice to evaluate the feasibility of the hypoxia-responsive VEGF gene expression system in vivo. The results suggest that the hypoxia-responsive VEGF gene expression system is promising to prepare artificial 3D tissues in regenerative medicine."

Journal • Transplantation • VEGFA

Supramolecular nanovesicles for synergistic glucose starvation and hypoxia-activated gene therapy of cancer. (PubMed, Nanoscale) - "The host-guest interactions (that mediate nano-assembly formation) and hypoxia-activatable promoters act as two locks to keep glucose oxidase (GOx) and a therapeutic plasmid (RTP801::p53) inside supramolecular gold nanovesicles (Au NVs). Upon initial dissociation of the host-guest interactions and hence Au NVs by cancer-specific reactive oxygen species (ROS), GOx is released to consume glucose and oxygen, generate H2O2 and induce the hypoxic TME, which act as the two keys for triggering burst payload release and promoter activation, thus allowing synergistic starvation and gene therapy of cancer. This "dual-lock" supramolecular nanomedicine exhibited integrated therapeutic effects in vitro and in vivo for tumor suppression."

Journal • Gene Therapies • Oncology

RTP801 regulates motor cortex synaptic transmission and learning. (PubMed, Exp Neurol) - "Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity and motor learning. They will help to understand its role in neurodegenerative disorders where RTP801 levels are detrimentally upregulated."

Journal • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease • NTRK2

Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease. (PubMed, Cell Death Dis) - "These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis."

Journal • Huntington's Disease • Movement Disorders • NTRK2

RNA therapeutics in ophthalmology - translation to clinical trials. (PubMed, Exp Eye Res) - "This review provides a detailed insight into the recent developments and clinical trials that have been conducted for several gene-silencing therapies, including ISTH0036, SYL040012, SYL1001, PF-04523655, Sirna-027, QR-110, QR-1123, QR-421a and IONIS-FB-L in glaucoma, dry eye disease, age-related macular degeneration, diabetic macular oedema and various inherited retinal diseases. Our aim is to explore the potential of these drugs whilst evaluating their associated advantages and disadvantages, and to discuss the future translation of RNA therapeutics in ophthalmology."

Clinical • Journal • Review • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Diabetic Macular Edema • Dry Age-related Macular Degeneration • Dry Eye Disease • Glaucoma • Macular Degeneration • Macular Edema • Ocular Infections • Ophthalmology • Retinal Disorders

The stress response protein REDD1 as a causal factor for oxidative stress in diabetic retinopathy. (PubMed, Free Radic Biol Med) - "It is well established that REDD1 mediates the cellular response to a number of diverse stressors through repression of the central metabolic regulator known as mechanistic target of rapamycin complex 1 (mTORC1)...Furthermore, early proof-of-concept clinical trials have found a degree of success in combating ischemic retinal disease through intravitreal delivery of an siRNA targeting the REDD1 mRNA. Overall, REDD1-associated signaling represents an intriguing target for novel clinical therapies that go beyond addressing the symptoms of diabetes by targeting the underlying molecular mechanisms that contribute to DR."

Journal • Review • Diabetes • Diabetic Retinopathy • Metabolic Disorders • Ophthalmology • Retinal Disorders

[VIRTUAL] RTP801 MEDIATES SYNAPTIC PLASTICITY VIA EXTRACELLULAR VESICLES (ADPD 2021) - "All these data propose neuronal EVs as potential neuroprotective agents and RTP801 as a therapeutic target to prevent synaptic plasticity impairment and neurodegeneration."

Alzheimer's Disease • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease

Is REDD1 a metabolic double agent? Lessons from physiology and pathology. (PubMed, Am J Physiol Cell Physiol) - "In this review, we decipher several mechanisms that make REDD1 a likely metabolic double agent depending on its duration of expression in different physiological and pathological contexts. We also discuss the role played by REDD1 in the crosstalk between the Akt/mTOR signaling pathway and the energetic metabolism."

Journal • CNS Disorders • Depression • Diabetes • Genetic Disorders • Immunology • Metabolic Disorders • Obesity • Oncology • Psychiatry

The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. (PubMed) - Pharm Res - "...The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3)...Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development."

Journal • Review • Biosimilar • Gastrointestinal Cancer • Hepatitis C Virus • Immunology • Oncology • Ophthalmology • Pancreatic Cancer • Renal Disease

Effects of siRNA-Mediated Knockdown of GSK3β on Retinal Ganglion Cell Survival and Neurite/Axon Growth. (PubMed, Cells) - "Adult mixed retinal cell cultures, prepared from rats at five days after optic nerve crush (ONC) to activate retinal glia, were treated with siRNA to GSK3β (siGSK3β) alone or in combination with siRTP801 and RGC survival and neurite outgrowth were quantified in the presence and absence of Rapamycin or inhibitory Nogo-A peptides. Knockdown of RTP801 increased both RGC survival and axon regeneration, whilst the combined knockdown of GSK3β and RTP801 significantly increased RGC survival, neurite outgrowth, and axon regeneration over and above that observed for siGSK3β or siRTP801 alone. These results suggest that GSK3β suppression promotes RGC survival and axon initiation whilst, when in combination with RTP801, it also enhanced disinhibited axon elongation."

Journal

Progress on Ocular siRNA Gene Silencing Therapy and Drug Delivery Systems. (PubMed, Fundam Clin Pharmacol) - "RNA interference (RNAi) is being increasingly used in the treatment of these disorders with siRNA drugs, bevasiranib, AGN211745 and PF-04523655 for AMD, and SYL040012 and QPI-1007 for glaucoma. Compared with the non-viral vectors, viral vectors have limited payload capacity and potential immunogenicity. This review summarizes the progress of the ocular siRNA gene silencing therapy by focusing on siRNA drugs for AMD and glaucoma already used in clinical research, the main routes of drug delivery, and the non-viral vectors for siRNA drugs."

Journal • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Gene Therapies • Genetic Disorders • Glaucoma • Macular Degeneration • Ophthalmology • Rare Diseases • Retinal Disorders

Clinical Role of Epigenetics and Network Analysis in Eye Diseases: A Translational Science Review. (PubMed, J Ophthalmol) - "PF-04523655, a 19-nucleotide methylated double-stranded siRNA targeting the RTP80 gene, showed a dose-related improvement in best-corrected visual acuity (BCVA) in patients affected by diabetic macular edema. The observed results support a clinical network-based research program aimed to clarify the role of epigenetic regulators in the development of ocular diseases and personalized therapy."

Clinical • Journal • Review • CD24 • GSTP1 • MMP2