Lewy Body Dementia (LBD) Drug Discovery Service

Lewy body diseases (LBD) share alpha-synuclein (AS) aggregation and Lewy body (LB) formation as their key pathogenic events. The identification of molecular pathways that lead to AS oligomerization and further aggregation is fundamental to the successful design and development of treatments for important neurodegenerative diseases such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Creative Biolabs provides professional services for LBD research, a one-stop shop from in vitro to in vivo studies done by research scientists with long experience in the field.

Overview of LBD

LBD includes DLB and Parkinson's disease dementia (PDD). LBD belongs to the group of synucleinopathies and is characterized by the abnormal accumulation and deposition of misfolded and aggregated alpha-synuclein (α-syn) giving rise to Lewy bodies and Lewy neurites. The clinical manifestations of LBD include visual hallucinations, cognitive fluctuations, extrapyramidal symptoms, and neuro stability sensitivity. Treatment for LBD is mostly symptomatic, as there are no drugs to improve the disease. LBD are multifactorial disorders where the disease-associated phenotype develops as a result of the complex interaction between genetic and environmental factors.

Biomarker for LBD

With the emergence of disease-modifying therapies, early diagnostic markers for degenerative dementia are becoming increasingly important. Biomarkers are molecules that represent or indicate the particular signature of a physiological or pathophysiological state and that can be easily accessed and quantified. Reliable LBD biomarkers are needed to initiate treatment at a possible early pathophysiological stage.

• DNA Methylation Pattern as a Potential Biomarker for LBD

DNA modification is a promising biomarker for neurodegenerative diseases. In some epigenome studies, global DNA methylation abnormalities in PD and DLB brains have been identified.

• Histone Modification Patterns as Alternative Epigenetic Biomarkers for LBD

Systematic studies are needed to determine the dynamics of histone remodeling in different brain regions during the occurrence and development of LBD. Only in this way can the effective application of histone acetylation modification therapy be possible.

• Candidate Biomarkers for LBD

Many studies have attempted to identify epigenetic marks as biomarkers for DLB. The biomarker candidates should be considered carefully. Well-designed replication studies are needed to validate the initial data and to identify strong biomarker candidates for DLB.

Molecular Mechanisms in LBD

There is strong evidence for the role of synuclein aggregation in the pathogenesis of LBD. Synuclein is considered the major building block of LBs. Mitochondrial dysfunction is thought to be partly responsible for oxidative stress, which is an important factor in the loss of preference cells in certain groups of neurons in the brain. The ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP) are two of the most important mechanisms for repairing or removing abnormal proteins in cells. Alternative splicing is a versatile and widespread mechanism for the generation of multiple mRNAs from a single transcript. Creative Biolabs provides mechanism of action (MoA) studies to facilitate drug discovery and development in LBD.

Fig.1 Proposed pathogenic mechanisms of α-syn-related Lewy body formation in PD. (Kim, et al., 2014)

Therapeutic Strategies for LBD

Currently available symptom treatment strategies are based on monoaminergic, cholinergic, and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD. Disease-modifying approaches are aimed at preventing, slowing, or ameliorating the production, aggregation, and deposition of pathological proteins. Other clinical trials to alter the disease are using drugs to enhance insulin signaling, stem cell therapy, amyloid reduction pathology, and gene therapy.

• Transmitter-Based Therapies

Currently, cholinesterase inhibitors (ChEIs) are the mainstay of treatment options for LBD.

• Treatment of Visual Hallucinations

For patients with visual hallucinations and related symptoms, general strategies should be attempted such as optimizing vision, psychoeducation (i.e., providing education and information to those seeking or receiving mental health services), cognitive behavioral therapy, the workup for delirium, and reduction of dopaminergic drugs. Other treatments for visual hallucinations and related symptoms electroconvulsive therapy (ECT) and include morphine.

• α-Synuclein Immunotherapy

An emerging treatment approach has been α-synuclein immunotherapy. Immunotherapy is a broad concept that includes treatments that induce, strengthen, or suppress the immune system.

• Amyloid Strategies

As amyloid pathology has a prominent role in LBD development, strategies to reduce Aβ toxicity might be relevant in this context.

• Stem Cell Therapy

Recently, cerebrolysin (CBL) was an adjunct to neuronal stem cell (NSC) therapy. The study showed that CBL treatment enhanced NSCs survival and ameliorated behavioral deficits.

• Gene Therapy

Gene therapy of intracellular scFv is being explored to detect and remove intracellular α-synuclein aggregates.

Creative Biolabs' reliable LBD research and drug development services minimize your risk and timeline, maximize the performance of your project and save your resources. We offer our technical expertise and experience to provide traceable, customizable solutions. Please feel free to contact us for your LBD research.

Reference

1. Kim, D.; et al. What is the clinical significance of cerebrospinal fluid biomarkers in Parkinson's disease? Is the significance diagnostic or prognostic? Experimental Neurobiology. 2014, 23(4): 352.