Review
Pharmacology & Pharmacy
Thomas Lee Moore, Giovanna Pannuzzo, Gabriella Costabile, Anna Lisa Palange, Raffaele Spano, Miguel Ferreira, Adriana Carol Eleonora Graziano, Paolo Decuzzi, Venera Cardile
Summary: Nanomedicines are being investigated as vehicles to deliver therapeutics into the brain for the treatment of rare neurodevelopmental disorders such as Krabbe disease. This article discusses the challenges and potential solutions for nanoparticle delivery to the brain, and emphasizes the impact it can have on treating various neurological disorders.
ADVANCED DRUG DELIVERY REVIEWS
(2023)
Article
Multidisciplinary Sciences
Michael C. Babcock, Christina R. Mikulka, Bing Wang, Sanjay Chandriani, Sundeep Chandra, Yue Xu, Katherine Webster, Ying Feng, Hemanth R. Nelvagal, Alex Giaramita, Bryan K. Yip, Melanie Lo, Xuntian Jiang, Qi Chao, Josh C. Woloszynek, Yuqiao Shen, Shripad Bhagwat, Mark S. Sands, Brett E. Crawford
Summary: A selective small molecule inhibitor that reduces toxic substance levels in the nervous system has shown potential therapeutic effects in mouse models, but exhibited negative impacts in wild-type mice, indicating the need for further research.
SCIENTIFIC REPORTS
(2021)
Article
Clinical Neurology
Naoko Inamura, Shinji Go, Takashi Watanabe, Hiroshi Takase, Nobuyuki Takakura, Atsuo Nakayama, Hirohide Takebayashi, Junko Matsuda, Yasushi Enokido
Summary: Krabbe disease, caused by the deficiency of lysosomal galactosylceramidase activity, is a demyelinating disease with early-onset cerebral demyelination. The reduced expression of microRNA-219 in KD OLs plays a role in the pathogenesis of the disease, and miR-219 may have therapeutic potential for treating KD OL pathologies.
Article
Cell Biology
Dar-Shong Lin, Yu-Wen Huang, Tsung-Han Lee, Lung Chang, Zon-Darr Huang, Tsu-Yen Wu, Tuan-Jen Wang, Che-Sheng Ho
Summary: This study demonstrates the therapeutic efficacy of the mTOR inhibitor rapamycin in treating globoid cell leukodystrophy, a neurodegenerative disease. Rapamycin inhibits neuroinflammation, demyelination, and disease progression, leading to improved brain function.
Article
Neurosciences
Allison M. Bradbury, Ernesto R. Bongarzone, Mark S. Sands
Summary: Krabbe disease is a lysosomal storage disease characterized by demyelination, most commonly in its infantile form. It is caused by a deficiency of the acid hydrolase galactosylceramidase (GALC). Hematopoietic stem cell transplantation can slow the progression of the disease, but more effective treatments are still needed to combat this devastating condition.
NEUROSCIENCE LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Nayibe Tatiana Sanchez-Alvarez, Paula Katherine Bautista-Nino, Juanita Trejos-Suarez, Norma Cecilia Serrano-Diaz
Summary: Metachromatic leukodystrophy is a neurological disease that affects public health. This research focuses on the use of metformin as a treatment to counteract the effects of enzyme deficiencies and sulfatide accumulation. The study found that transfected human Schwann cells showed increased cell reactive oxygen species production when exposed to sulfatides, and sulfatides affected mitochondrial bioenergetics in these cells. Treatment with metformin restored the metabolic activity of the cells and decreased ROS production.
Article
Neurosciences
Emilie Audouard, Valentin Oger, Beatrix Meha, Nathalie Cartier, Caroline Sevin, Francoise Piguet
Summary: Metachromatic leukodystrophy is a lysosomal storage disorder caused by a deficiency of arylsulfatase A, leading to myelin degeneration in the nervous system. Current treatments are ineffective for the most common late infantile form of the disease. Gene therapy has shown promise in alleviating symptoms in animal models and improving brain pathology in the short term, suggesting potential for use in rapidly progressing forms of the disease.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Lorenza Vantaggiato, Enxhi Shaba, Alfonso Carleo, Daiana Bezzini, Giovanna Pannuzzo, Alice Luddi, Paola Piomboni, Luca Bini, Laura Bianchi
Summary: The proteomic profile of the KD-carrier brain suggests dysfunctions associated with neurodegeneration, including alterations in (mechano) signaling and intracellular trafficking, proteostasis and lipid metabolism, myelin composition and turnover, as well as mitochondrion and energy supply dysfunctions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Diego Iacono, Shunsuke Koga, Hui Peng, Arulmani Manavalan, Jessica Daiker, Monica Castanedes-Casey, Nicholas B. Martin, Aimee R. Herdt, Michael H. Gelb, Dennis W. Dickson, Chris W. Lee
Summary: Krabbe Disease is an autosomal recessive disorder caused by mutations in the GALC gene, leading to demyelination in the central and peripheral nervous systems. Research shows that GALC protein is mainly located in oligodendrocytes in the cerebral white matter, associated with myelination. Neuropathological changes associated with KD onset and severity were observed.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Biochemistry & Molecular Biology
Maria B. Cachon-Gonzalez, Chao Zhao, Robin J. Franklin, Timothy M. Cox
Summary: Infantile Krabbe disease is a rapidly progressing and fatal disorder caused by a deficiency of the lysosomal enzyme beta-galactocerebrosidase. The upregulation of inflammatory pathways, specifically caspase-11 and associated genes, is found in nervous tissue of affected individuals. This inflammatory response is also observed in other neurodegenerative diseases, indicating its potential as a therapeutic target.
HUMAN MOLECULAR GENETICS
(2023)
Article
Biotechnology & Applied Microbiology
Yedda Li, Christopher A. Miller, Lauren K. Shea, Xuntian Jiang, Miguel A. Guzman, Randy J. Chandler, Sai M. Ramakrishnan, Stephanie N. Smith, Charles P. Venditti, Carole A. Vogler, Daniel S. Ory, Timothy J. Ley, Mark S. Sands
Summary: Replacing AAV2/5 with AAV2/9 significantly improved motor function endpoints in a murine model of Krabbe disease, but led to the development of hepatocellular carcinoma in most treated mice. The study highlights the value of AAV-based combination therapy for Krabbe disease, but also underscores the importance of considering other therapies or comorbidities before proceeding with AAV-mediated gene therapy in human trials.
Article
Pharmacology & Pharmacy
Martina Messina, Paul Gissen
Summary: Metachromatic leukodystrophy (MLD) is a rare autosomal recessive disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA), leading to demyelination in the central and peripheral nervous systems. MLD can be categorized into early- and late-onset subtypes, with the early onset subtype having a more severe progression and shorter life expectancy. Previously, there were no effective treatments for MLD due to the blood-brain barrier hindering systemic enzyme replacement therapy. However, recent studies have shown the potential of hematopoietic stem cell transplantation for late-onset MLD subtype.
Review
Biotechnology & Applied Microbiology
Gregory Heller, Allison M. Bradbury, Mark S. Sands, Ernesto R. Bongarzone
Summary: Krabbe disease is a lysosomal storage disease caused by mutations in the galc gene, leading to developmental issues and premature death in children. Current treatments for lysosomal storage diseases are insufficient, and there is no cure available. However, recent advancements in understanding the pathology of Krabbe disease have led to gene therapy-based clinical trials that may provide new treatment options. This review discusses the progress made in understanding Krabbe disease and its potential implications for the treatment of other lysosomal storage diseases.
Article
Neurosciences
Qinghua Wang, Jifeng Piao, Yulong Li, Huiru Tu, Dingyi Lv, Libin Hu, Run Zhang, Zhenzhong Zhong
Summary: This study found that bone marrow mesenchymal stem cells (BMSCs) can alleviate intracerebral hemorrhage (ICH) by inhibiting microglial pyroptosis through the secretion of C1q/tumor necrosis factor-related protein 3 (CTRP3). BMSCs also suppressed neuroinflammation by inhibiting the activation of the Syk signaling pathway and promoting the activation of the PI3K/AKT signaling pathway. These findings provide a new therapeutic strategy for the treatment of ICH.
EXPERIMENTAL NEUROLOGY
(2023)
Review
Biotechnology & Applied Microbiology
Francesca Tucci, Samantha Scaramuzza, Alessandro Aiuti, Alessandra Mortellaro
Summary: Gene transfer into autologous HSPCs shows potential in treating monogenic blood disorders and metabolic diseases. Two products based on HSPCs have been approved in the EU, with more expected in the near future. Despite achievements, challenges remain for HSPC-GT.