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Zhang, Tan, Xin Wang, Hannah M. Jester, Xueyan Zhou, and Tao Ma. "Characterization of Apathy-Like Behaviors in Mouse Models of Down Syndrome." Journal of Alzheimer's Disease 101, no. 4 (October 8, 2024): 1217–26. http://dx.doi.org/10.3233/jad-240675.
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Background: Apathy is a state of decreased interest, lack of initiative, reduced goal-directed activity and blunted emotional responses. Apathy is one of the most common neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) and is also relatively omnipresent in individuals with Down syndrome (DS). Little is known about the apathy-like behaviors in rodent models of AD and DS. Objective: This study aimed to characterize apathy-like behaviors with aging in two established DS mouse models: Ts65Dn and Dp16. Methods: A battery of behavioral tests including nestlet shredding, marble burying, nest building, and burrowing were performed to examine apathy-like behaviors. Individual z-scores for each mouse for each test, and a composite z-score of apathy-like behavior were analyzed for all mice from these behavioral tests. Results: Analysis of individual test results and composite z-score revealed significant apathy-like behaviors in Ts65Dn mice compared to WT controls. In contrast, Dp16 mice did not exhibit significant apathy-like behaviors. Conclusions: Our study is the first to characterize apathy-like behaviors in mouse models of DS with aging and highlights the difference between Ts65Dn and Dp16 DS model mice regarding apathy-like manifestations with aging.
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Bartesaghi, Renata, Stefano Vicari, and William C. Mobley. "Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders." Annual Review of Pharmacology and Toxicology 62, no. 1 (January 6, 2022): 211–33. http://dx.doi.org/10.1146/annurev-pharmtox-041521-103641.
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Those with Down syndrome (DS)—trisomy for chromosome 21—are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.
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Deckert, Jutta, Jenny Thirlway, Yun-Hee Park, Ho Young Song, Chul-Woong Chung, Xuesong Wang, Zhenshan Zhang, and Robert J. Lutz. "Abstract 1753: IKS014, a HER2-targeting antibody drug conjugate incorporating novel bioconjugation and tumor-selective linker technology with improved in vivo efficacy and tolerability." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1753. http://dx.doi.org/10.1158/1538-7445.am2022-1753.
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Abstract HER2 has long been a target of high interest for antibody and antibody drug conjugate (ADC) therapeutics due to its well-documented overexpression in breast, gastric and lung cancer. While trastuzumab and ado-trastuzumab emtansine (T-DM1) have become an integral part of treatment paradigms for HER2-positive cancer, the more recent approvals of the fam-trastuzumab deruxtecan (DS-8201) ADC and the Fc-engineered margetuximab antibody have highlighted the potential for continued improvement over existing HER2-targeting therapies. IKS014 is a HER2-directed ADC that incorporates site-directed conjugation and tumor-selective glucuronide-trigger linker technology to reduce systemic off-target toxicity while maximizing efficient intracellular lysosomal payload release, thus holding the promise of a wider therapeutic index. IKS014 was generated by site-specific conjugation via a proprietary beta-glucuronide linker to the microtubule agent MMAF with a drug-to-antibody ratio (DAR) 2. In vitro and in vivo activity was evaluated in HER2-positive preclinical models with varying HER2 expression levels in comparison to benchmark ADCs. Pharmacokinetics (PK) and tolerability studies were conducted in rodent and cynomolgus monkey. IKS014 conjugation resulted in a homogeneous ADC with defined DAR and good physio-chemical properties. In vitro, IKS014 demonstrated dose dependent specific cytotoxicity against Her2-positive cell lines. In JIMT-1 breast cancer xenografts with moderate HER2-expression (HER2 IHC 2+), IKS014 causes complete regressions at a single dose of 5 mg/kg and partial regressions at 1 mg/kg, while T-DM1 results in only tumor growth inhibition even at 15 mg/kg. Anti-tumor efficacy of IKS014 in NCI-N87 (HER2 3+) gastric xenografts is comparable to DS-8201 but superior to T-DM1 at equivalent single doses ranging from 1 to 5 mg/kg. In a HER2-positive patient-derived gastric cancer model (HER2 2+), IKS014 was highly active at 5mg/kg Q2W x2, while T-DM1 was inactive at the same dosing schedule. IKS014 demonstrated stable PK with a terminal half-life of 8.7 days in rat and 4.6 days in monkey, and DAR 2 was maintained for up to 4 weeks. In cynomolgus monkeys, IKS014 was tolerated at 12 mg/kg single dose and 5 mg/kg repeat dose without ocular or lung toxicity findings. IKS014 was highly efficacious against HER2-positive tumor xenografts in vivo, including models with moderate target expression, and compared favorably to clinically validated benchmark ADCs. This improved preclinical efficacy combined with stable PK and good tolerability profile warrants further development of this novel ADC for HER2-positive cancers. Citation Format: Jutta Deckert, Jenny Thirlway, Yun-Hee Park, Ho Young Song, Chul-Woong Chung, Xuesong Wang, Zhenshan Zhang, Robert J. Lutz. IKS014, a HER2-targeting antibody drug conjugate incorporating novel bioconjugation and tumor-selective linker technology with improved in vivo efficacy and tolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1753.
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Zhang, Xichen, Michael W. Epperly, Mark A. Kay, Zhi-Ying Chen, Tracy Smith, Darcy Franicola, Benjamin Greenberger, Paavani Komanduri, and Joel S. Greenberger. "Minicircle Plasmid Containing the Human Manganese Superoxide Dismutase (MnSOD) Transgene Confers Radioprotection to Hematopoietic Progenitor Cell Line 32Dcl3." Blood 110, no. 11 (November 16, 2007): 5138. http://dx.doi.org/10.1182/blood.v110.11.5138.5138.
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Abstract Manganese superoxide dismutase plasmid/liposomes (MnSOD-PL) delivered by intratracheal, intraesophageal, or intraoral routes in rodent models has been demonstrated to confer organ specific ionizing irradiation protection. In addition intravenous injections of MnSOD-PL protect mice from whole body irradiation. Currently a seven week phase I/II clinical trial is in progress in lung cancer patients consisting of twice weekly swallowed MnSOD-PL for protection of the esophagus from chemoradiotherapy damage. To prepare for a potential clinical trial of systemic MnSOD-PL for radioprotection in humans, plasmid bacterial sequences were removed to diminish the immune response. The human MnSOD transgene attached to a CMV promoter and a poly A tail was inserted in the site between Spe I and Xho I into a eukaryotic expression cassette located in the p2ØC31 plasmid. The plasmid contains an endonuclease I-SceI gene which can be cleaved resulting in the formation of two minicircle plasmids. The smaller minicircle contains the eukaryotic expression cassette but no bacterial sequences while the larger minicircle plasmid contains the plasmid bacterial backbone. The minicircle MnSOD was purified and then co-transfected into 32Dcl3 murine hematopoietic progenitor cells with a plasmid containing the neo gene. Cells were selected in G418 (50μg/ml G418) and cloned by limiting dilution into 96 well plates. The clones were expanded and analyzed by PCR for the presence of the human MnSOD transgene using primers specific for the human MnSOD. One clone was chosen and the MnSOD biochemical activity was determined. The 32Dcl3 cells had a specific MnSOD activity of 2.7 ± 0.1 U/mg protein compared to 5.8 ± 0.5 U/mg protein for the 32D-mc-MnSOD clone (p=0.0039). To determine if the MnSOD transgene in the minicircle DNA retained radioprotective capacity 32D-mc-MnSOD, a clone transfected with a pRK5 plasmid containing the human MnSOD transgene (2C6), and parent 32Dcl3 cells were irradiated to doses of 0–8 Gy then grown at 37° C for 7 days at which time colonies of greater than 50 cells were counted. The data was analyzed by linear quadratic and single-hit, multi-target models. The 32D-mc-MnSOD cells were more radioresistant than 32Dcl3 cells as demonstrated by an increased shoulder on the irradiation survival curve (n = 4.8 ± 0.2 compared to 1.5 ± 0.5, respectively, p = 0.0078). In contrast, there was no significant reduction in the shoulder of the survival curve comparing 32D-mc-MnSOD and 2C6 (n = 4.8 ± 0.2 and 4.6 ± 0.2, respectively). In vivo C57BL/6NHsd mice received intraoral mc-MnSOD-PL, mc-DS-red-PL, MnSOD-PL or Blank-PL, swallowed the plasmid/liposome complexes and were then irradiated 24 hr later along with control mice to 31 Gy to the esophagus. Mice receiving mc-MnSOD-PL had increased survival compared to both the control mice or mice treated with mc-DS-red-PL (p = 0.0099 or 0.0391, respectively). There was significant and equivalent improved survival of mice injected with mc-MnSOD-PL compared to full length MnSOD-PL. Therefore minicircle DNA containing the human MnSOD transgene confers undiminished radioprotection to cells in vitro and the esophagus in vivo compared to a fully intact plasmid containing the MnSOD transgene.
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Jin, Shanshan, Xiaochen Zhang, Yunlu Jia, Yongchao Dai, Fengwei Xu, Yongfeng Huang, Xun Wang, et al. "The design, preclinical study and phase I dose escalation plan of a HER2 targeted immunoliposome (HF-K1) for HER2 low solid tumor treatment." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 3035. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.3035.
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3035 Background: Doxorubicin liposome formulations are being used extensively in the clinic in anthracycline chemotherapy with reduced cardiotoxicity. However, they did not improve clinical outcome because the cancer cell uptake of PEG-coated liposomes is poor. So, the concept of coating antibodies on the liposome surface was initiated and they were named immunoliposomes. There have been numerous studies conducted world-wide for the development of immunoliposomes but none have progressed to late-stage development. Our work draws on the experiences of these prior studies with a new perspective. Since the mechanism of immunoliposomes is similar to those of ADCs, we sought to compare immunoliposomes with ADCs containing the same cancer cell binding domain, for target cell binding capability, binding affinity as well as in vivo distribution, tumor tissue accumulation, and anti-tumor activities. The lessons learned from the success of many ADC products may be applicable to the development of immunoliposomes. Methods: The antibody to liposome ratio (ALR) and the drug to lipid ratio (DLR) of the immunoliposomes were selected by in vitro and in vivo anti-cancer activity screening. Cell lines with different HER2 expression levels were used to study immunoliposome binding, cell uptake, drug delivery and cytotoxicity. PK, drug distribution, efficacy and toxicities studies were conducted in respective CDX and PDX mice and non-rodent models. Based on these studies, a phase I dose escalation study plan was designed and the study is now ongoing. Results: HF-K1 was designed to have an average of 10 anti-HER2 Fab on each liposome surface and approximately 2300 doxorubicin molecules inside. The equivalent drug to antibody ratio (DAR) is 230. HF-K1 can bind to cancer cells with different levels of HER2 expression with similar kinetics and induces cells death at IC50s of 0.35-6.46 μg/ml Fab concentration. It has a long circulation behavior and enhanced permeability and retention (EPR) in tumor tissues. The clearance T1/2 of HF-K1 in mice and monkey is 12.78 h and 47.12 h, respectively. Evaluation of HF-K1 activity in vivo showed significant tumor growth inhibition >95% at the equivalent antibody dose of 3.6 mg/kg in various mouse tumor models including HER2 low and HER2 very low (HER2-). Similar activities were shown by ADCs including T-DM1 and DS-8201a at about 10 mg/kg. Conclusions: The encouraging preclinical data supported a clinical trial starting with dose escalation at equivalent antibody doses of 0.72 mg/m2, 2.16 mg/m2, 5.4 mg/m2, 10.8 mg/m2, 16.2 mg/m2, and 21.6 mg/m2. The study is ongoing to determine the safety, tolerability, PK, and preliminary antitumor efficacy in participants with HER2 positive or HER2 low expression advanced solid tumors (NCT05861895). Clinical trial information: NCT05861895 .
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Nonoguchi, Hannah A., Timothy Wee Shang Kouo, Sandhya Kortagere, Joshua Hillman, David L. Boyle, and Chitra D. Mandyam. "Lipopolysaccharide Exposure Differentially Alters Plasma and Brain Inflammatory Markers in Adult Male and Female Rats." Brain Sciences 12, no. 8 (July 24, 2022): 972. http://dx.doi.org/10.3390/brainsci12080972.
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Humans and rodents have sexually dimorphic immune responses, which could influence the brain’s response to a systemic inflammatory insult. Lipopolysaccharide (LPS) is a stimulator of the innate immune system and is routinely used in animal models to study blood–brain barrier (BBB) dysfunction under inflammatory conditions. Therefore, we examined whether inflammatory response to LPS and the associated BBB disruption differed in male and female adult rats. Rats were treated with saline or two injections of 1 mg/kg LPS and studied 24 h after the second LPS injection. Plasma isolated from trunk blood and brain tissue homogenates of the prefrontal cortex (PFC), dorsal striatum (DS), hippocampus, and cerebellum were analyzed for cytokines and chemokines using a 9-plex panel from Meso Scale Discovery. BBB disruption was analyzed with tight junction proteins claudin-5 and VE-cadherin via Western blotting and VEGF by ELISA. This allowed us to compare sex differences in the levels of individual cytokines as well as associations among cytokines and expression of tight junction proteins between the plasma and specific brain regions. Higher levels of interferon-γ, interleukin-10 (IL-10), IL-13, IL-4, CXCL-1, and VEGF in the plasma were revealed compared to the brain homogenates, and higher levels of TNFα, IL-1β, IL-6, and IL-5 in the PFC were seen compared with plasma and other brain regions in males. Females showed higher levels of plasma CXCL1 and VEGF compared to males, and males showed higher levels of PFC TNFα, IL-6, IL-4, and VEGF compared to females. LPS induced significant increases in plasma cytokines and VEGF in both sexes. LPS did not significantly alter cytokines in brain tissue homogenates, however, it increased chemokines in the PFC, DS, and hippocampus. In the PFC, LPS produced BBB disruption, which is evident as reduced expression of claudin-5 in males and reduced expression of VE-cadherin in both sexes. Taken together, our results reveal significant sex differences in pro-inflammatory cytokine and chemokine levels in plasma and brain that were associated with BBB disruption after LPS, and validate the use of multiplex assay for plasma and brain tissue samples.
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Venkateshappa, Chandregowda, Kishore Narayanan, Rashmi Nair, Aravind AB, Ramakishore VP Putta, Jwala Nagaraj, Megha Goyal, et al. "Abstract 4432: A highly differentiated A2AR inhibitor for potential use in cancer therapy." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4432. http://dx.doi.org/10.1158/1538-7445.am2023-4432.
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Abstract As a potent immunosuppressor adenosine is essential for maintaining tissue homeostasis and preventing an overzealous immune response during inflammation and infection. However, adenosine generated within the tumor microenvironment by the action of ectonucleotides hinders the immune reaction towards cancer cells by signaling through adenosine receptors such as high affinity A2AR expressed on immune cells. Tumors evade the immune response by usurping pathways that negatively regulate normal immune responses. Resistance to inhibition of immune checkpoint targets arises because of an upregulation in the expression of the CD39-CD73 axis and the resulting increase in production of adenosine in the tumor microenvironment. Inhibition of either adenosine generation or signaling by inhibition of A2AR along with other immune activation strategies have been shown to be effective therapeutic approaches. In view of this, we sought to discover and develop novel small molecule inhibitors that dually target A2AR and an immuno-suppressive ligand expressed in the tumor microenvironment. Aurigene’s dual inhibitors exhibit potent inhibition of both A2AR and an immuno-suppressive target of relevance in respective biochemical assays. Potent biochemical activity translated into rescue of chemokines and IL-2 in human PBMCs. Lead compounds exhibited desirable drug-like properties and excellent pharmacokinetic exposure in rodents. In a syngeneic tumor model, lead compounds demonstrated significant tumor growth inhibition. Anti-tumor efficacy correlated well with tumor drug levels and modulation of pharmacodynamic markers. In summary, we have identified first-in-class dual inhibitors with good drug like properties, which showed significant antitumor efficacy. Evaluation of these lead compounds in additional tumor models and in vivo toxicity studies will be presented. Citation Format: Chandregowda Venkateshappa, Kishore Narayanan, Rashmi Nair, Aravind AB, Ramakishore VP Putta, Jwala Nagaraj, Megha Goyal, Vijay Kamal Ahuja, Amith A Dhudashiya, Samiulla DS, Girish Daginakatte, Thomas Antony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. A highly differentiated A2AR inhibitor for potential use in cancer therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4432.
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Khare, Leena, Ramulu Poddutoori, Subhendu Mukherjee, Samiulla DS, Devaraja TS, Sivapriya Marappan, Shilpa Nayak, et al. "Abstract B172: Potent anti-tumor activity of a selective and orally bioavailable reversible covalent CDK12 inhibitor." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): B172. http://dx.doi.org/10.1158/1535-7163.targ-23-b172.
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Abstract Cyclin-dependent kinase 12 (CDK12), in association with Cyclin K (CycK), regulates the elongation of transcription by modifying RNA polymerase II (RNAP II) through phosphorylation at Serine 2 (pS2) in the C-terminal domain, CDK12 plays an important role in maintaining genomic stability by modulating crucial cellular processes such as DNA damage response, splicing, and pre-mRNA processing. Overexpression of CDK12 has been observed in various tumor types, suggesting its potential oncogenic properties like other kinases involved in transcription. Given its significance in transcription and RNA processing, CDK12 has emerged as a promising therapeutic target for cancer treatment. We have identified a highly potent and selective reversible covalent inhibitor of CDK12, AU-22880, which exhibits significant anti-proliferative activity across various cancer cell lines. The covalent mode of action and on-target activity of AU-22880 were confirmed in a CDK12 target engagement assay and selective pS2 RNAPII inhibition respectively in a cellular context. Additionally, it has shown synergistic activity in combination with several standard-of-care agents in breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer cell lines. AU-22880 shows desirable ADME-PK properties and demonstrates excellent anti-tumor activity in xenograft models. In the HCC-70 TNBC xenograft model, AU-22880 demonstrated anti-tumor efficacy at well-tolerated doses. A pharmacokinetic-pharmacodynamic (PK-PD) study revealed dose-dependent target engagement, as evidenced by the inhibition of pS2 RNAPII and DNA damage repair (DDR) genes. Furthermore, AU-22880 exhibited good tolerability in rodents, dog, and monkeys at exposure levels that demonstrated efficacy. Efficacy of AU-22880 in combination with approved SOCs targeting DDR pathway are currently being investigated. The findings reported here highlight the promising therapeutic potential of AU-22880, both as a monotherapy and in combination with existing treatments for the treatment of cancers characterized by DDR dysregulation. Citation Format: Leena Khare, Ramulu Poddutoori, Subhendu Mukherjee, Samiulla DS, Devaraja TS, Sivapriya Marappan, Shilpa Nayak, Sasirekha Sivakumar, Lakshmi Kaza, Suraj Tgore, Amit Dhudashiya, Raghavendra NR, Bhargav Gunnepalli, Aravind A B, Amith A, Charamanna KB, Thomas Antony, Kavitha Nellore, Girish Daginakatte, Shekar Chelur, Sanjeev Giri, Murali Ramachandra, Susanta Samajdar. Potent anti-tumor activity of a selective and orally bioavailable reversible covalent CDK12 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B172.
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Farrell, Clíona, Paige Mumford, Millie Beament, Gloria Lau, Yixing Wu, Marion Pellen, Monika Rataj Baniowska, et al. "Modelling of the development and response to amyloid‐β accumulation in the context of trisomy21 in the rodent brain." Alzheimer's & Dementia 19, S12 (December 2023). http://dx.doi.org/10.1002/alz.075677.
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AbstractBackgroundIndividuals who have Down syndrome (DS), a genetic condition caused by having three copies of chromosome 21, frequently develop early‐onset Alzheimer’s disease (AD). This is caused by the additional copy of the APP gene, located on chromosome 21, which leads to a raised abundance of amyloid‐β. However, significant evidence demonstrates that the additional copy of other genes on the chromosome modifies the accumulation and response to amyloid‐β. Here we present a series of rodent preclinical models of AD‐DS, which we use to investigate this biology and can be used to test potential therapeutic approaches.MethodsWe previously crossed mouse models of DS with the AppNL‐F model of amyloid‐β accumulation; demonstrating that three copies of a region of chromosome 21 containing 38 genes is sufficient to reduce the accumulation of amyloid‐β. Here we present new data from a cross of the Dp1Tyb DS mouse model with an App gene knock‐out (to normalise the number of copies of this gene) and novel DS‐AD rodent models in which the endogenous App gene has been partially humanized (Dup(Rno11)‐APP‐H3 and Ts68Yah) compared with DS model controls (Dup(Rno11) and Ts66Yah). Brain material from these models at a range of ages was analyzed by western blot, biochemical fractionation and MSD assay, and immunohistology to study APP processing and amyloid‐β accumulation. We used MSD assay and immunofluorescence to study the response to accumulating amyloid‐β with a focus on the response of microglia, neuroinflammation and break‐down of the blood‐brain barrier.ResultsOur data indicate that three copies of App contribute to altered microglia biology in the Dp1Tyb mouse model of DS and that partial humanization of the App gene in DS rodent models leads to alterations in the processing of APP, and results in raised levels of human amyloid‐β in the brain.ConclusionThese new model systems of DS‐AD amyloid‐β biology can be used to better understand the early development of AD in people who have DS and to test the safety and efficacy of new therapies for this important group of individuals who are at extremely high risk of developing early onset dementia.
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Farrell, Clíona, Paige Mumford, and Frances K. Wiseman. "Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches." Frontiers in Neuroscience 16 (June 7, 2022). http://dx.doi.org/10.3389/fnins.2022.909669.
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There are an estimated 6 million people with Down syndrome (DS) worldwide. In developed countries, the vast majority of these individuals will develop Alzheimer's disease neuropathology characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles within the brain, which leads to the early onset of dementia (AD-DS) and reduced life-expectancy. The mean age of onset of clinical dementia is ~55 years and by the age of 80, approaching 100% of individuals with DS will have a dementia diagnosis. DS is caused by trisomy of chromosome 21 (Hsa21) thus an additional copy of a gene(s) on the chromosome must cause the development of AD neuropathology and dementia. Indeed, triplication of the gene APP which encodes the amyloid precursor protein is sufficient and necessary for early onset AD (EOAD), both in people who have and do not have DS. However, triplication of other genes on Hsa21 leads to profound differences in neurodevelopment resulting in intellectual disability, elevated incidence of epilepsy and perturbations to the immune system. This different biology may impact on how AD neuropathology and dementia develops in people who have DS. Indeed, genes on Hsa21 other than APP when in three-copies can modulate AD-pathogenesis in mouse preclinical models. Understanding this biology better is critical to inform drug selection for AD prevention and therapy trials for people who have DS. Here we will review rodent preclinical models of AD-DS and how these can be used for both in vivo and ex vivo (cultured cells and organotypic slice cultures) studies to understand the mechanisms that contribute to the early development of AD in people who have DS and test the utility of treatments to prevent or delay the development of disease.
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Chang, Pishan, Marta Pérez-González, Jessica Constable, Daniel Bush, Karen Cleverley, Victor L. J. Tybulewicz, Elizabeth M. C. Fisher, and Matthew C. Walker. "Neuronal oscillations in cognition: Down syndrome as a model of mouse to human translation." Neuroscientist, September 24, 2024. http://dx.doi.org/10.1177/10738584241271414.
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Down syndrome (DS), a prevalent cognitive disorder resulting from trisomy of human chromosome 21 (Hsa21), poses a significant global health concern. Affecting approximately 1 in 800 live births worldwide, DS is the leading genetic cause of intellectual disability and a major predisposing factor for early-onset Alzheimer’s dementia. The estimated global population of individuals with DS is 6 million, with increasing prevalence due to advances in DS health care. Global efforts are dedicated to unraveling the mechanisms behind the varied clinical outcomes in DS. Recent studies on DS mouse models reveal disrupted neuronal circuits, providing insights into DS pathologies. Yet, translating these findings to humans faces challenges due to limited systematic electrophysiological analyses directly comparing human and mouse. Additionally, disparities in experimental procedures between the two species pose hurdles to successful translation. This review provides a concise overview of neuronal oscillations in human and rodent cognition. Focusing on recent DS mouse model studies, we highlight disruptions in associated brain function. We discuss various electrophysiological paradigms and suggest avenues for exploring molecular dysfunctions contributing to DS-related cognitive impairments. Deciphering neuronal oscillation intricacies holds promise for targeted therapies to alleviate cognitive disabilities in DS individuals.
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Sasaki, Masato, Mina Delawary, Hidetaka Sakurai, Hideki Kobayashi, Naoki Nakao, Hiromi Tsuru, Yumiko Fukushima, et al. "Novel LCAT (Lecithin:Cholesterol Acyltransferase) Activator DS-8190a Prevents the Progression of Plaque Accumulation in Atherosclerosis Models." Arteriosclerosis, Thrombosis, and Vascular Biology, October 22, 2020. http://dx.doi.org/10.1161/atvbaha.120.314516.
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Objective: Enhancement of LCAT (lecithin:cholesterol acyltransferase) activity has possibility to be beneficial for atherosclerosis. To evaluate this concept, we characterized our novel, orally administered, small-molecule LCAT activator DS-8190a, which was created from high-throughput screening and subsequent derivatization. We also focused on its mechanism of LCAT activation and the therapeutic activity with improvement of HDL (high-density lipoprotein) functionality. Approach and Results: DS-8190a activated human and cynomolgus monkey but not mouse LCAT enzymes in vitro. DS-8190a was orally administered to cynomolgus monkeys and dose dependently increased LCAT activity (ca. 2.1-fold in 3 mg/kg group on day 7), resulting in HDL cholesterol elevation without drastic changes of non-HDL cholesterol. Atheroprotective effects were then evaluated using Ldl-r KO × hLcat Tg mice fed a Western diet for 8 weeks. DS-8190a treatment achieved significant reduction of atherosclerotic lesion area (48.3% reduction in 10 mg/kg treatment group). Furthermore, we conducted reverse cholesterol transport study using Ldl-r KO × hLcat Tg mice intraperitoneally injected with J774A.1 cells loaded with [ 3 H]-cholesterol and confirmed significant increases of [ 3 H] count in plasma (1.4-fold) and feces (1.4-fold on day 2 and 1.5-fold on day3) in the DS-8190a–treated group. With regard to the molecular mechanism involved, direct binding of DS-8190a to human LCAT protein was confirmed by 2 different approaches: affinity purification by DS-8190a–immobilized beads and thermal shift assay. In addition, the candidate binding site of DS-8190a in human LCAT protein was identified by photoaffinity labeling. Conclusions: This study demonstrates the potential of DS-8190a as a novel therapeutic for atherosclerosis. This is also the first report describing that a small-molecule direct LCAT activator achieved HDL cholesterol elevation in monkey and reduction of atherosclerotic lesion area with enhanced HDL function in rodent.
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Wong, Helen, Jordan M. Buck, Curtis Borski, Jessica T. Pafford, Bailey N. Keller, Ryan A. Milstead, Jessica L. Hanson, Jerry A. Stitzel, and Charles A. Hoeffer. "RCAN1 knockout and overexpression recapitulate an ensemble of rest-activity and circadian disruptions characteristic of Down syndrome, Alzheimer’s disease, and normative aging." Journal of Neurodevelopmental Disorders 14, no. 1 (May 24, 2022). http://dx.doi.org/10.1186/s11689-022-09444-y.
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Abstract Background Regulator of calcineurin 1 (RCAN1) is overexpressed in Down syndrome (DS), but RCAN1 levels are also increased in Alzheimer’s disease (AD) and normal aging. AD is highly comorbid among individuals with DS and is characterized in part by progressive neurodegeneration that resembles accelerated aging. Importantly, abnormal RCAN1 levels have been demonstrated to promote memory deficits and pathophysiology that appear symptomatic of DS, AD, and aging. Anomalous diurnal rest-activity patterns and circadian rhythm disruptions are also common in DS, AD, and aging and have been implicated in facilitating age-related cognitive decline and AD progression. However, no prior studies have assessed whether RCAN1 dysregulation may also promote the age-associated alteration of rest-activity profiles and circadian rhythms, which could in turn contribute to neurodegeneration in DS, AD, and aging. Methods The present study examined the impacts of RCAN1 deficiency and overexpression on the photic entrainment, circadian periodicity, intensity and distribution, diurnal patterning, and circadian rhythmicity of wheel running in young (3–6 months old) and aged (9–14 months old) mice of both sexes. Results We found that daily RCAN1 levels in the hippocampus and suprachiasmatic nucleus (SCN) of light-entrained young mice are generally constant and that balanced RCAN1 expression is necessary for normal circadian locomotor activity rhythms. While the light-entrained diurnal period was unaltered, RCAN1-null and RCAN1-overexpressing mice displayed lengthened endogenous (free-running) circadian periods like mouse models of AD and aging. In light-entrained young mice, RCAN1 deficiency and overexpression also recapitulated the general hypoactivity, diurnal rest-wake pattern fragmentation, and attenuated amplitudes of circadian activity rhythms reported in DS, preclinical and clinical AD, healthily aging individuals, and rodent models thereof. Under constant darkness, RCAN1-null and RCAN1-overexpressing mice displayed altered locomotor behavior indicating circadian clock dysfunction. Using the Dp(16)1Yey/+ (Dp16) mouse model for DS, which expresses three copies of Rcan1, we found reduced wheel running activity and rhythmicity in both light-entrained and free-running young Dp16 mice like young RCAN1-overexpressing mice. Critically, these diurnal and circadian deficits were rescued in part or entirely by restoring Rcan1 to two copies in Dp16 mice. We also found that RCAN1 deficiency but not RCAN1 overexpression altered protein levels of the clock gene Bmal1 in the SCN. Conclusions Collectively, this study’s findings suggest that both loss and aberrant gain of RCAN1 precipitate anomalous light-entrained diurnal and circadian activity patterns emblematic of DS, AD, and possibly aging.
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Hill, Lisa J., Hannah F. Botfield, Ghazala Begum, Omar Qureshi, Vasanthy Vigneswara, Imran Masood, Nicholas M. Barnes, Lars Bruce, and Ann Logan. "ILB® resolves inflammatory scarring and promotes functional tissue repair." npj Regenerative Medicine 6, no. 1 (January 7, 2021). http://dx.doi.org/10.1038/s41536-020-00110-2.
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AbstractFibrotic disease is a major cause of mortality worldwide, with fibrosis arising from prolonged inflammation and aberrant extracellular matrix dynamics. Compromised cellular and tissue repair processes following injury, infection, metabolic dysfunction, autoimmune conditions and vascular diseases leave tissues susceptible to unresolved inflammation, fibrogenesis, loss of function and scarring. There has been limited clinical success with therapies for inflammatory and fibrotic diseases such that there remains a large unmet therapeutic need to restore normal tissue homoeostasis without detrimental side effects. We investigated the effects of a newly formulated low molecular weight dextran sulfate (LMW-DS), termed ILB®, to resolve inflammation and activate matrix remodelling in rodent and human disease models. We demonstrated modulation of the expression of multiple pro-inflammatory cytokines and chemokines in vitro together with scar resolution and improved matrix remodelling in vivo. Of particular relevance, we demonstrated that ILB® acts, in part, by downregulating transforming growth factor (TGF)β signalling genes and by altering gene expression relating to extracellular matrix dynamics, leading to tissue remodelling, reduced fibrosis and functional tissue regeneration. These observations indicate the potential of ILB® to alleviate fibrotic diseases.
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Ramos-Mondragon, Roberto, Chunling Chen, Julie Ziobro, Yan Chen, Shuyun Wang, Eric N. Jimenez-Vazquez, Luis Lopez-Santiago, Jack Parent, and Lori L. Isom. "Abstract 12541: Development of a Transgenic Rabbit Model of Dravet Syndrome." Circulation 146, Suppl_1 (November 8, 2022). http://dx.doi.org/10.1161/circ.146.suppl_1.12541.
Full textAbstract:
Introduction: Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of death in patients with epilepsy. While SUDEP mechanisms are not understood, there is evidence to implicate autonomic dysfunction and cardiac arrhythmias. Loss-of-function variants in SCN1A are linked to Dravet syndrome (DS). Importantly, SCN1A is expressed in both heart and brain in humans and rodents. Studies on Scn1a+/- DS mice and induced pluripotent stem cell (iPSC)-derived cardiac myocytes from DS patients show altered cardiac electrophysiology that serves as substrates for arrhythmias. However, no mouse or iPSC model can completely replicate the human DS phenotype. Hypothesis: Cardiac arrhythmias contribute to the mechanisms of SUDEP in a rabbit model of DS. Methods: We generate a New Zealand White (NZW) rabbit Scn1a deletion model using CRISPR-Cas9 gene editing. Rabbits were tested using video EEG/ECG telemetry as well as surface ECG under anesthesia. Optical mapping studies were performed in isolated hearts and patch clamp electrophysiology was performed in acutely isolated cardiac myocytes. Results: NZW Scn1a-/- kits died by postnatal day (P) 7-9 and showed bradycardia, long QT intervals, and AP prolongation. Cardiac myocytes isolated from NZW Scn1a+/- kits showed increased late sodium current compared to WT. We did not observe behavioral seizures or arrhythmias in NZW Scn1a+/- rabbits, which live normal life spans and breed normally. These data suggested, like mouse models, that the DS rabbit phenotype may be background strain dependent. To test this hypothesis, we crossed Scn1a+/- NZW rabbits to the Dutch Belted (DB) strain. We found that F1:NZW x DB Scn1a+/- rabbits have spontaneous seizures as well as pre- and post-ictal cardiac arrhythmia as assessed by video/EEG/ECG telemetry. Approximately 22% of the kits undergo premature death. Severe seizures are observed in adult animals, but to date no adults have died during seizures. Conclusions: F1:NZW x DB Scn1a+/- rabbits model DS in terms of seizures and SUDEP and are an optimal model to investigate neuro-cardiac mechanisms of SUDEP as well as to develop novel therapeutics for DS. To our knowledge, this is the first transgenic large animal model of a developmental and epileptic encephalopathy