Review
Geriatrics & Gerontology
William M. Pardridge
Summary: Parkinson's disease is a neurodegenerative disease characterized by the degeneration of nigral-striatal neurons, formation of alpha-synuclein aggregates, and neuro-inflammation. These processes can be treated with biologics by re-engineering their structure to enable transport across the blood-brain barrier (BBB) via receptor-mediated transcytosis (RMT). This review discusses the re-engineering of different classes of biologics for BBB delivery and also highlights the potential of non-viral gene therapy using lipid nanoparticles.
FRONTIERS IN AGING NEUROSCIENCE
(2023)
Article
Chemistry, Medicinal
Joshua Yang, Weijun Ou, Nataraj Jagadeesan, Juste Simanauskaite, Jiahong Sun, Demi Castellanos, David H. Cribbs, Rachita K. Sumbria
Summary: A new therapeutic approach utilizing the fusion of erythropoietin and a chimeric transferrin receptor monoclonal antibody was found to reduce amyloidosis and phospho-tau accumulation in a mouse model of Alzheimer's disease. This treatment also alleviated behavioral abnormalities, demonstrating its potential as a therapeutic intervention.
Article
Multidisciplinary Sciences
Sarah Mustaly-Kalimi, Wacey Gallegos, Robert A. Marr, Alice Gilman-Sachs, Daniel A. Peterson, Israel Sekler, Grace E. Stutzmann
Summary: Impairments in Ca2+ signaling disrupt lysosomal acidification and contribute to pathological protein aggregation in neurodegenerative disorders like AD. Targeting the RyR-Ca2+ pathway could be a potential therapeutic intervention.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Pharmacology & Pharmacy
Weijun Ou, Yuu Ohno, Joshua Yang, Devaraj Chandrashekar, Tamara Abdullah, Jiahong Sun, Riley Murphy, Chuli Roules, Nataraj Jagadeesan, David H. Cribbs, Rachita K. Sumbria
Summary: TNF-alpha inhibitors play a crucial role in the pathology of Alzheimer's disease, and delivering them to the brain can enhance their therapeutic effects. In this study, the fusion of TNF-alpha receptor with a transferrin receptor antibody showed better therapeutic outcomes in aged APP/PS1 mice compared to other TNF-alpha inhibitors, without causing any hematological or iron-related dysregulation.
Review
Pharmacology & Pharmacy
Hiroyuki Sonoda, Kenichi Takahashi, Kohtaro Minami, Toru Hirato, Tatsuyoshi Yamamoto, Sairei So, Kazunori Tanizawa, Mathias Schmidt, Yuji Sato
Summary: Enzyme replacement therapy (ERT) is effective for somatic symptoms of lysosomal storage diseases (LSDs), but not for central nervous system (CNS)-related symptoms due to the blood-brain barrier (BBB). Efforts have been made to modify enzymes to cross the BBB via receptor-mediated transcytosis (RMT) and treat CNS neuronopathy.
Article
Neurosciences
Gillian Bonvicini, Stina Syvanen, Ken G. G. Andersson, Merja Haaparanta-Solin, Francisco Lopez-Picon, Dag Sehlin
Summary: This study investigates the efficacy of using transferrin receptor (TfR) as a targeting strategy to transport amyloid-beta (Aβ) immunoPET ligands across the blood-brain barrier (BBB). The results indicate that the affinity to TfR affects the efficiency of crossing the BBB, and this method shows potential for imaging Aβ pathology in rats.
TRANSLATIONAL NEURODEGENERATION
(2022)
Article
Clinical Neurology
Tobias Gustavsson, Nicole G. Metzendorf, Elin Wik, Sahar Roshanbin, Ulrika Julku, Aikaterini Chourlia, Per Nilsson, Ken G. Andersson, Hanna Laudon, Greta Hultqvist, Stina Syvanen, Dag Sehlin
Summary: In this study, the therapeutic efficacy of A beta targeting antibody RmAb158 and its bispecific variant RmAb158-scFv8D3 was compared. Both antibodies achieved positive effects in long-term treatment, but the bispecific antibody's limited plasma exposure may hinder its application in chronic therapy as a result of interactions with TfR or the immune system.
ALZHEIMERS RESEARCH & THERAPY
(2023)
Article
Chemistry, Medicinal
William M. Pardridge, Tom Chou
Summary: This study examines the receptor-mediated transcytosis of monoclonal antibodies targeting transferrin receptor or insulin receptor at the blood-brain barrier, using mathematical models to analyze and predict the transport process. The optimal rates of receptor association with the targeted antibodies are highlighted as crucial factors determining the efficiency of transcytosis.
Article
Geriatrics & Gerontology
Zhi-ting Chen, Chu-zhui Pan, Xing-lin Ruan, Li-ping Lei, Sheng-mei Lin, Yin-zhou Wang, Zhen-Hua Zhao
Summary: This study found that the levels of ferritin and TfR in plasma neural-derived exosomes of patients with PD were significantly higher, suggesting that they may serve as potential biomarkers for PD.
FRONTIERS IN AGING NEUROSCIENCE
(2023)
Article
Immunology
Weijun Ou, Joshua Yang, Juste Simanauskaite, Matthew Choi, Demi M. Castellanos, Rudy Chang, Jiahong Sun, Nataraj Jagadeesan, Karen D. Parfitt, David H. Cribbs, Rachita K. Sumbria
Summary: The study demonstrated that both BBB-penetrating and non-BBB-penetrating biologic TNF inhibitors showed therapeutic effects in the PS19 mouse model of tauopathy, significantly improving neuronal health and phosphorylated tau levels.
JOURNAL OF NEUROINFLAMMATION
(2021)
Article
Radiology, Nuclear Medicine & Medical Imaging
N. Stergiou, T. E. Wuensche, M. Schreurs, I. Mes, M. Verlaan, E. J. M. Kooijman, A. D. Windhorst, L. Helboe, S. Vergo, S. Christensen, A. A. Asuni, A. Jensen, G. A. M. S. Van Dongen, B. Bang-Andersen, D. J. Vugts, W. Beaino
Summary: This study used Zr-89-immuno-PET to evaluate the targeting and distribution of a bispecific brain-shuttle IgG, Adu-8D3, as a potential theranostic for AD. The results showed high specific uptake of Adu-8D3 in the brain, indicating its potential for early detection of A beta plaque pathology.
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
(2023)
Review
Biochemistry & Molecular Biology
Deepa Gautam, Ulhas P. Naik, Meghna U. Naik, Santosh K. Yadav, Rameshwar Nath Chaurasia, Debabrata Dash
Summary: This paper explores the role of platelets in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, as well as the critical role of glutamate receptors in the pathophysiology of these diseases. By reviewing data from clinical trials, animal models, and cellular studies, it reveals the involvement of glutamate receptor dysfunction in neurodegenerative processes and provides an overview of current treatments, including glutamate receptor antagonists, for AD and PD.
Review
Biochemistry & Molecular Biology
Rebecca Maechtel, Fanni Annamaria Boros, Jan Philipp Dobert, Philipp Arnold, Friederike Zunke
Summary: Lysosomes are acidic organelles responsible for recycling cellular components and can cause lysosomal dysfunction and LSDs when there is reduced enzymatic activity. Neurons are particularly susceptible to lysosomal dysfunction, leading to neurological symptoms. There are genetic associations between LSDs and Parkinson's disease, indicating common cellular mechanisms.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Review
Multidisciplinary Sciences
Sureshbabu Ram Kumar Pandian, Kevin Kumar Vijayakumar, Sankaranarayanan Murugesan, Selvaraj Kunjiappan
Summary: The function of the brain can be affected by various factors such as infection, tumor, and stroke. Alzheimer's disease (AD), Parkinson's disease (PD), dementia, brain cancer, seizures, mental disorders, and other movement disorders are common diseases associated with altered brain function. However, the blood-brain barrier (BBB) and cerebrospinal fluid (CSF) barrier pose challenges for the treatment of central nervous system (CNS) diseases. Liposomes show promise in delivering drugs to specific brain cells, but face obstacles such as immunogenicity.
Article
Chemistry, Medicinal
William M. Pardridge
Summary: Biologic drugs are large molecule pharmaceuticals that cannot cross the blood-brain barrier. They can be re-engineered for BBB transport as IgG fusion proteins. The kinetics of BBB transport can be quantified with mathematical models.