Dementia with Lewy bodies (DLB) is defined as the toxic accumulation of α-synuclein protein inside brain cells, and DLB represents a particular presentation of a pathogenic α-synucleinopathies (Lewy body disease). Neurodegeneration in DLB patients is clinically accompanied by behavioral and psychological abnormalities. DLB overlaps neurochemically and pathologically with Alzheimer's disease (AD) while also sharing features with Parkinson's disease (PD) and Parkinson's disease dementia (PDD) [1].
Existing therapies
DLB is a complex disease with numerous sequelae that should all be considered while treating DLB patients. The primary clinical characteristics of DLB are:
Dementia
Parkinsonism
Hallucinations
Cognitive fluctuations
Rapid eye movement sleep behavior disorders
Most DLB patients are treated with the help of symptomatic treatment. The existing symptomatic treatment for DLB varies in its effectiveness. In DLB, acetylcholinesterase inhibitors and L-dopa replacement therapy may partially regulate cognitive and motor symptoms, respectively. Selective serotonin reuptake inhibitors and antipsychotics manage the behavioral symptoms of DLB but exacerbate the motor symptoms. Thus, disease-modifying and curative therapies to stop the disease progression and effectively treat various symptoms remain an unmet need. Finding a treatment for DLB that can stop neuronal loss and reduce cognitive, motor, and behavioral symptoms is a major challenge[2], [3].
No treatment for DLB can reduce the levels of neurotoxic proteins like α-synuclein and stop neuronal death. Neurotoxic proteins can be degraded by the process of autophagy (elimination of damaged or redundant cellular components). It has been shown that neurodegeneration causes impairment in the autophagy process, which prevents the breakdown of protein aggregates, including misfolded α-synuclein. Tyrosine kinase inhibitors (TKIs) promote α-synuclein, amyloid-β, and hyperphosphorylated tau degradation through autophagy in PD and AD models [1].
Tyrosine kinase inhibitors – Nilotinib, Bosutinib, K0706
The three TKIs – nilotinib, bosutinib, and K0706 are being investigated by the same researchers from Georgetown University. TKIs have shown promise in treating several diseases, including chronic myeloid leukemia (CML) by inducing autophagy. Evidence suggests that neurodegenerative diseases affect autophagy, which prevents the degradation of neurotoxic proteins including α-synuclein, amyloid-β, and tau. TKIs could provide neuroprotection for DLB patients by removing these neurotoxic proteins. Also, TKIs have demonstrated a reduction in inflammation by modulating several neuroinflammation markers in animal studies [1], [4].
Nilotinib
Nilotinib is a chemotherapeutic agent approved for the treatment of CML. The TKIs may prove to be effective in the treatment of DLB, PDD, and AD. In PD mice models, nilotinib reduces the neurodegenerative effects caused by toxic proteins such as α-synuclein and hyperphosphorylated tau on the brain and cognitive function. Preclinical evidence for potential advantages of nilotinib includes:
Autophagic clearance of neurotoxic proteins (α-synuclein, tau, and amyloid-β)
Reduced loss of dopaminergic neurons
Protective effects on neural cells
Targeting kinases involved in the hyperphosphorylation of tau to clear them from neurons.
Nilotinib has also been proven to have the ability to lower the neuroinflammation associated with neurodegenerative diseases. These findings suggested that nilotinib may be a disease-modifying therapy for α-synucleinopathies [1], [4].
Bosutinib
Bosutinib is another TKI that targets Src (non-receptor protein tyrosine kinase) and c-Abelson (Abl) tyrosine kinases and is also an approved drug for CML. Like nilotinib, the postulated mechanism in DLB is the stimulation of autophagy to facilitate the removal of neurotoxic proteins. Bosutinib is delaying the onset of neurodegenerative diseases (AD, DLB, and PDD) and reduces the damage caused to neurons [1], [4].
K0706
K0706 is a new Abl TKI being developed by Sun Pharma for the treatment of adult patients with CML. K0706 may be an option for patients with intolerance or resistance to the first-line TKIs like nilotinib and bosutinib. K0706 was recently shown to be well tolerated in PD patients and has been shown in animal models to decrease dopaminergic cell death and improve behavioral outcomes [4]. A randomized, double-blind, placebo-controlled phase 2 trial evaluating the safety and tolerability of K0706 and studying the impact of K0706 on clinical outcomes in DLB (identifier: NCT03996460) [5].
The bottom line
DLB is a multisystem disorder that manifests itself in various ways. Patients are not favored by a treatment plan that only addresses the cognitive aspects of the disease. Patients should instead receive education on how to spot the signs of this multisystem involvement. Currently, there are no disease-modifying treatments. TKI is one of the newly emerging therapeutic options for DLB that can improve the overall status of the disease. However, further clinical studies on the long-term safety and efficacy of TKIs are required in DLB patients alone rather than combining DLB with other neurodegenerative conditions in clinical studies. In addition, detailed profiling of the expressions and activities of degenerative modifications of protein kinase linked to neurodegenerative disease is vital to consider TKIs as a disease-modifying approach for DLB.
References
E. D. Pope, L. Cordes, J. Shi, Z. Mari, B. Decourt, and M. N. Sabbagh, “Dementia with Lewy bodies: Emerging drug targets and therapeutics,” Expert Opin Investig Drugs, vol. 30, no. 6, pp. 603–609, Jun. 2021, doi: 10.1080/13543784.2021.1916913.
I. G. McKeith et al., “Diagnosis and management of dementia with Lewy bodies,” Neurology, vol. 89, no. 1, pp. 88–100, Jul. 2017, doi: 10.1212/WNL.0000000000004058.
B. P. Boot, “Comprehensive treatment of dementia with Lewy bodies,” Alzheimer's Res Ther, vol. 7, no. 1, p. 45, 2015, doi: 10.1186/s13195-015-0128-z.
G. Lee, J. Cummings, B. Decourt, J. B. Leverenz, and M. N. Sabbagh, “Clinical drug development for dementia with Lewy bodies: past and present,” Expert Opin Investig Drugs, vol. 28, no. 11, pp. 951–965, Nov. 2019, doi: 10.1080/13543784.2019.1681398.
F. P. MD, “A Randomized, Double-Blind, Placebo-controlled Study to Evaluate the Impact of K0706 on Safety, Tolerability, Pharmacokinetics and Pharmacodynamics and Clinical Outcomes in Dementia With Lewy Bodies (DLB),” clinicaltrials.gov, Clinical trial registration NCT03996460, Oct. 2022. Accessed: Jan. 08, 2023. [https://clinicaltrials.gov/ct2/show/NCT03996460]. Available: https://clinicaltrials.gov/ct2/show/NCT03996460
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