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Can drug repurposing find new compounds with activity for dementia with Lewy bodies?

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder characterized by the abnormal accumulation of Lewy bodies. The cognitive function usually fluctuates including episodic disorientation and reduced vigilance. DLB is characterized by recurrent visual hallucinations and parkinsonism along with the ability to "play out his or her dreams" while sleeping, which is termed rapid eye movement sleep behavior disorder. When compared to other dementias, DLB is more likely to result in higher mortality, poor quality of life, and a faster rate of functional deterioration. DLB is also associated with increased healthcare costs and higher caregiver burden [1].


Existing state of affairs


Dementia with Lewy bodies

Currently, limited symptomatic treatments are available, primarily acetylcholinesterase inhibitors, antipsychotics, antidepressants, psychostimulants, electroconvulsive therapy, memantine, etc., to treat cognitive impairment, psychotic symptoms, hallucinations, and motor symptoms. However, none of the existing therapies address the underlying cause of the disease, which includes protein accumulation in the brain. For a while, DLB symptoms like cognitive impairment, neuropsychiatric symptoms, sleep disorders, and motor symptoms may improve with treatment. However, even though patients respond well to symptomatic treatment, they continue to deteriorate. Hence, there is an urgent need for better therapies to enhance the subpar clinical outcomes and improve the quality of life of DLB patients [1].


What is drug repurposing?


Drug repurposing has been effective in finding new treatments for a variety of conditions that can then be quickly implemented in clinical practice. The use of proven pharmacological molecules for new therapeutic purposes is known as drug repurposing. For several conditions, such as various cancers and other forms of dementia, this has been recommended. Drug repurposing, the investigation of existing drugs for new therapeutic uses, has emerged as a sensible and well-liked technique to find new treatment alternatives as the drug development process is expensive and lengthy. As a result, it is important to find prospective agents that might be suitable for repurposing in DLB treatment [1].


Ambroxol


In several European nations, ambroxol, a mucolytic drug, is used to treat throat pain and break up phlegm in respiratory infections. Ambroxol is an expectorant that has been given over the counter for more than 30 years to both adults and children in more than 50 different countries. The Mahuran Lab discovered ambroxol in a high throughput screen as a pharmacological chaperone of glucocerebrosidase (GCase) [2].


According to an increasing body of preclinical evidence in Parkinson’s disease, ambroxol exhibits neuroprotective effects through overexpression of GCase, which results in a reduction of α-synuclein pathology and an increase in mitochondrial function. Ambroxol has been found to function as a GCase chaperone. A chaperone is a small molecule that binds to proteins to stabilize them and direct proteins along the proper pathways for folding.


Ambroxol is associated with the upregulation of GCase through the transcription factor EB pathway. Ambroxol acts by:

  • Inhibiting autophagy

  • Triggering the secretory pathway

  • Stimulating lysosomal exocytosis

  • Promoting correct post-translational protein folding

  • Attenuating the unfolded protein response

  • Apoptosis rescue via controlling cytochrome-C, caspase-9, and caspase-3 expression


In animal models of Parkinson’s disease, ambroxol improves behavioral and motor impairments. These improvements may be mediated by the attenuation of the pathological effects of α-synuclein and the restoration of the dopaminergic system. A growing body of research has also shown that ambroxol can increase GCase levels in Parkinson’s disease animal and cell culture models. Surprisingly, mice treated with Ambroxol had higher levels of GCase and lower levels of α-synuclein aggregation in their brain region [1], [2].


Ongoing trials


A Phase-2 randomized, placebo-controlled trial in DLB is currently being conducted to examine how the GCase-enhancing chaperone ambroxol affects patients with prodromal and early DLB in terms of cognition, functional decline, and neuropsychiatric symptoms (identifier: NCT04588285) [3]. Another randomized, placebo-controlled, double-blind study investigating the safety and effectiveness of ambroxol for the treatment of cognitive impairments associated with Lewy Body Dementia (identifier: NCT04405596) [4].


Outlook


The lack of any disease-modifying treatments emphasizes the clear and urgent need for new therapies for DLB. Also, DLB imposes an enormous burden of disease globally in terms of its negative effects on quality of life and mortality. Ambroxol appears to be a highly promising agent for repurposing, and there is enough data to move it forward into Phase-2 and Phase-3 clinical trials for DLB patients. Further clinical trials are warranted to study the long-term safety and efficacy of ambroxol in treating DLB by modifying the underlying causes of the disease and a better understanding of its mechanisms of action.


References

  1. J. T. O’Brien et al., “RENEWAL: Repurposing study to find new compounds with Activity for Lewy body dementia—an international Delphi consensus,” Alzheimer’s Research & Therapy, vol. 14, no. 1, p. 169, Nov. 2022, doi: 10.1186/s13195-022-01103-7.

  2. Helse Fonna, “A Clinical Trial to Demonstrate Clinical Efficacy on Cognitive, Neuropsychiatric and Functional Outcomes of Ambroxol in New and Early Patients With Prodromal and Mild Dementia With Lewy bodies,” clinicaltrials.gov, Clinical trial registration NCT04588285, May 2021. Accessed: Jan. 05, 2023. [https://clinicaltrials.gov/ct2/show/NCT04588285?term=Ambroxol&cond=Dementia+with+Lewy+Bodies&draw=2&rank=2]. Available: https://clinicaltrials.gov/ct2/show/NCT04588285

  3. S. Pasternak, “Ambroxol as a Novel Disease Modifying Treatment for Lewy Body Dementia,” clinicaltrials.gov, Clinical trial registration NCT04405596, Aug. 2022. Accessed: Jan. 05, 2023. [https://clinicaltrials.gov/ct2/show/NCT04405596?term=Ambroxol&cond=Lewy+body+disease&draw=2&rank=1]. Available: https://clinicaltrials.gov/ct2/show/NCT04405596

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Collaborators

IIT Guwahati
University of Manchester
Rhenix Lifesciences
American university of Sharjah
IIT Delhi
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