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"Drug Repositioning in Neurodegenerative Diseases"

Updated: Nov 20

[1]Poly-pharmacology: Finding new tricks of an old dog: drug repositioning in neurodegenerative diseases


Drug repurposing, also known as drug repositioning or drug reprofiling, is essentially using “old” drugs to treat “new” diseases. Prompted in part by the high cost of developing new chemical entities, drug repurposing is becoming a novel way of discovering drugs to cure disease. As the scientific community’s knowledge about the molecular mechanisms underlying diseases expands, drug repurposing has emerged as a new strategy that involves using existing drugs originally developed for one disease to treat another disease. Thus, the time required for drug development is shorter, since preclinical and most clinical drug-safety trials can be eliminated for an approved drug. With drug repurposing: The old drug used to treat “disease A” can be used for a new purpose—to treat “disease B.” Medicines that are no longer used for their initial purpose regain their utility surprisingly as new medicines to treat new diseases. Examples include using thalidomide to treat multiple myeloma, chloroquine to treat autoimmune diseases, and chinoform to treat dementia and autism. This strategy has become invaluable in recent years, as drug pipelines of pharmaceutical industries have continued to shrink. In addition, pharmaceutical companies realize that many previously promising compounds fail to generate medicines for their intended uses. So why not use them for another purpose? That is, use them to treat other diseases that share similar biological pathways and molecular mechanisms. Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, polyglutamine diseases and amyotrophic lateral sclerosis, are a group of intractable diseases associated with ageing [1]. They are characterized by the progressive degeneration of neurons in various regions of the brain, resulting in neurological and psychiatric symptoms. Molecular genetics and biological studies have revealed that most neurodegenerative diseases are caused by protein misfolding and aggregation, so-called protein misfolding diseases, with similar intrinsic characteristics such as propagation by prion-like infectious mechanisms [2,3]. Therapeutic strategies targeting protein misfolding and aggregation are being explored extensively. However, the therapeutic agents currently approved by the Food and Drug Administration (FDA) or in clinical trials attempt to address disease symptoms and are largely aimed at ameliorating cognitive or motoric decline, but not at the mechanisms underlying the actual neurodegeneration and disease progression pathways [4]. Therapeutic agents that interfere with abnormal protein aggregation are required, but the traditional drug discovery approach has fallen short in developing novel candidates especially considering the long development times, cost and approvals required. The development of an intervention to slow or halt disease progression remains the greatest unmet therapeutic need in neurodegenerative disease [5]. Given the number of failures of various novel interventions in disease-modifying clinical trials, in combination with the ever-increasing costs and lengthy processes for drug development, attention is being turned to utilizing existing compounds approved for other indications as alternative treatments in neurodegenerative disease [6]. Advances of “omics” technologies in describing complex disease and drug-induced modification of biological pathways offer exciting opportunities for drug identification and repurposing as novel therapeutic strategies. Such approaches are more systematic than traditional modes of drug development. In addition, the integration of diverse chemoproteomics data offer new insights into disease biology that extend beyond drug discovery, by uncovering disparate biomedical networks including side-effects, drug targets and therapeutic classes that are associated with high-dimensional disease signatures [7-10]. The development of diseases, particularly the complex ones, involves several processes and pathways. Recent evidence in biological systems and overall clinical experience has revealed that single-target drugs may not always induce the desired effect on the disease process even if they successfully inhibit or activate a specific target, possibly because compensatory pathways undermine effectiveness. The exploration of new uses for already approved drugs provides a useful alternative to classical drug discovery technologies (6). The rationale of drug repositioning lies, in part, in the ability of small molecules to target distinct proteins in cells. Multiple pathways involved in disease initiation or progression that are considered unrelated to each other can thus be targeted by the same molecule. The concept of using a single drug to target multiple pathways has been dubbed “polypharmacology”. This contrasts with identification of one drug specific for one target, thereby reducing off-target toxicities. The development of anti-misfolding and anti-aggregation agents that are commonly effective against a wide range of neurodegenerative diseases is eagerly anticipated. Using the “omics” technologies, Curescience™ team is developing several innovative technologies and pipelines to mitigate neurodegenerative disease from novel and drug repurposing approaches.


Written by Siva Yadavalli, PhD, Scientist: Systems Biology & Drug Repurposing


References:

1. Marios Kritsilis, Sophia V. Rizou, Paraskevi N. Koutsoudaki, Konstantinos Evangelou, Vassilis G. Gorgoulis and Dimitrios Papadopoulos. Ageing, Cellular Senescence and Neurodegenerative Disease. Int. J. Mol. Sci. 2018, 19(10), 2937; doi: 10.3390/ijms19102937.

2. Caterina Peggion, Maria Catia Sorgato, and Alessandro Bertoli. Prions and Prion-Like Pathogens in Neurodegenerative Disorders. Pathogens. 2014 Mar; 3(1): 149–163.

3. Bess Frost and Marc I. Diamond. Prion-like Mechanisms in Neurodegenerative Diseases. Nat Rev Neurosci. 2010 Mar; 11(3): 155–159. doi: 10.1038/nrn2786.

4. Aaron D. Gitler, Paraminder Dhillon and James Shorter, Neurodegenerative disease: models, mechanisms, and a new hope. Disease Models & Mechanisms (2017) 10, 499-502 doi:10.1242/dmm.030205

5. Maria Laura Bolognesi. Neurodegenerative drug discovery: building on the past, looking to the future. Future Med. Chem. (2017) 9(8), 707–709.

6. Fernando Durães, Madalena Pinto and Emília Sousa. Old Drugs as New Treatments for Neurodegenerative Diseases. Pharmaceuticals 2018, 11, 44; doi: 10.3390/ph11020044.

7. Holly Matthews, James Hanison, and Niroshini Nirmalan. “Omics”-Informed Drug and Biomarker Discovery: Opportunities, Challenges and Future Perspectives. Proteomes. 2016 Sep; 4(3): 28.

8. Brian S. Hilbush, John H. Morrison, Warren G. Young, J. Gregor Sutcliffe,and Floyd E. Bloom. New Prospects and Strategies for Drug Target Discovery in Neurodegenerative Disorders. NeuroRx. 2005 Oct; 2(4): 627–637.

9. Hanqing Xue, Jie Li, Haozhe Xie, and Yadong Wang. Review of Drug Repositioning Approaches and Resources. Int J Biol Sci. 2018; 14(10): 1232–1244.

10. Jose A. Santiago, Virginie Bottero, and Judith A. Potashkin. Dissecting the Molecular Mechanisms of Neurodegenerative Diseases through Network Biology. Front Aging Neurosci. 2017; 9: 166.

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