Innovative Potential of AEX Compounds for Modulating α-Synuclein in Parkinson’s Disease

Background

Parkinson’s Disease (PD) is a neurodegenerative disorder marked by the progressive accumulation of α-synuclein aggregates, particularly the A53T mutant. This mutation exacerbates protein aggregation, leading to the formation of toxic inclusions known as Lewy bodies, which contribute to neuronal dysfunction and cell death. Therapeutic strategies targeting α-synuclein aggregation and its effects on neurite morphology and autophagy offer promise for treating PD.

Role of Cathepsin D in Neurodegeneration

Cathepsin D (CTSD) is a lysosomal protease crucial for degrading various substrates, including α-synuclein, amyloid precursor protein (APP), and tau, all of which tend to aggregate if not efficiently degraded. Genetic variants within the CTSD gene have been linked to neurodegenerative diseases like PD and Alzheimer’s Disease (AD). Recent studies highlight the role of CTSD in substrate degradation within autophagic pathways. However, its precise function in disease development requires further exploration.

Involvement of OX1R in Synucleinopathies

Orexin 1 Receptor (OX1R) is involved in regulating wakefulness and energy homeostasis. Emerging research indicates that OX1R may play a role in modulating neurodegenerative processes. In PD, the interaction between OX1R and α-synuclein dynamics could influence neuronal survival and function.

Targeting Alpha-Synuclein Aggregation

The α-synuclein A53T Parkinson’s Disease genetic cell based agonist neurite outgrowth assay by Eurofins assessed the impact of various AEX compounds on neurite outgrowth in SH-SY5Y neuronal cells expressing the human α-synuclein A53T mutant. Neurite outgrowth, a critical parameter of neuronal health, was measured using high-content imaging systems to determine the efficacy of AEX compounds.

Reducing α-synuclein aggregation or promoting its clearance can alleviate its toxic effects on neurons.

The effects of AEX compounds on neurite outgrowth, as well as their impact on CTSD and OX1R activities, provide insights into their potential to modulate the impact of α-synuclein.

Insights into key compounds

AEX-23: Its significant action as an OX1R agonist, combined with positive effects on neurite outgrowth at specific concentrations, suggests that it may modulate neuronal health through pathways influencing α-synuclein dynamics, making it a potential therapeutic candidate to improve neuronal connectivity and resilience in PD.

AEX-19: Its effects at low concentrations on neurite growth, coupled with significant OX1R agonist activity and a moderate increase in CTSD activity, suggest potential neuroprotective benefits in PD.

AEX-24: The significant increase in CTSD activity and agonist activity on OX1R suggest a potential to enhance α-synuclein degradation, highlighting its promising therapeutic impact on PD.

Conclusion

The AEX compounds, such as AEX-23 and AEX-19, which target OX1R, show promise in modulating the effects of α-synuclein on neurons, offering potential benefits in treating synucleinopathies like Parkinson’s Disease (PD).

AEX-19 and AEX-24 also present intriguing possibilities due to their effects on CTSD activity, suggesting pathways for reducing α-synuclein aggregation.

Further in vitro research and in vivo preclinical studies are necessary to elucidate the precise mechanisms, optimize dosing, and evaluate the long-term efficacy and safety of these compounds in preclinical and clinical settings.

Aexon Labs’ Commitment to Innovation

At Aexon Labs, our approach integrates the advantages of non-sulfonamide dual orexin receptor agonists and cathepsin inhibitors. This strategy balances receptor activation and prevents desensitization, enhancing patient safety and therapeutic efficacy. By targeting OX1R alongside α-synuclein, the AEX compounds mentioned above may offer a multifaceted therapeutic approach to ameliorate PD progression. Our commitment is to deliver innovative and safer therapeutic options for neurodegenerative disorders, setting a new standard in the treatment of these diseases.

References

Cullen, V., Lindfors, M., Ng, J., Paetau, A., Swinton, E., Kolodziej, P., Boston, H., Saftig, P., Woulfe, J., Feany, M.B., 2009. Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo. Molecular brain 2, 1–17. https://doi.org/ 10.1186/1756-6606-2-5

Drobny, A., Boros, F.A., Balta, D., Prieto Huarcaya, S., Caylioglu, D., Qazi, N., Vandrey, J., Schneider, Y., Dobert, J.P., Pitcairn, C., Mazzulli, J.R., Zunke, F., 2023. Reciprocal effects of alpha-synuclein aggregation and lysosomal homeostasis in synucleinopathy models. Transl Neurodegener 12, 31. https://doi.org/10.1186/s40035-023-00363-z

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Prieto Huarcaya, S., Drobny, A., Marques, A.R.A., Di Spiezio, A., Dobert, J.P., Balta, D., Werner, C., Rizo, T., Gallwitz, L., Bub, S., Stojkovska, I., Belur, N.R., Fogh, J., Mazzulli, J.R., Xiang, W., Fulzele, A., Dejung, M., Sauer, M., Winner, B., Rose-John, S., Arnold, P., Saftig, P., Zunke, F., 2022. Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models. Autophagy 18, 1127–1151. https://doi.org/10.1080/15548627.2022.2045534

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Major Breakthrough in Narcolepsy Treatment: Aexon Labs’ Dual Non-Sulfonamide Orexin Receptor Agonists

Aexon Labs is excited to announce a significant advancement in the treatment of narcolepsy and neurodegenerative diseases with the publication of our latest patent application (WO2024115797) by the World Intellectual Property Organization (WIPO). This new patent application introduces a novel series of dual non-sulfonamide orexin receptor agonists, representing a major leap forward compared to current treatments and other ongoing patent applications.

These innovative compounds are designed to target both orexin receptors (OX1R and OX2R), essential for maintaining wakefulness and regulating sleep patterns. By modulating these receptors, our dual agonists offer a unique approach to mitigating the symptoms of narcolepsy and slowing the progression of neurodegenerative diseases such as Parkinson’s .

A key differentiator of our compounds is their non-sulfonamide structure, which reduces the risk of side effects commonly associated with sulfonamide derivatives. This characteristic not only broadens their potential application but also enhances patient safety.

Moreover, these multitarget compounds incorporate a mechanism to inhibit Cathepsin H (CTSH), an enzyme implicated in the autoimmune destruction of orexin-producing neurons. By preventing this cellular destruction, our compounds not only address the symptoms but also target the underlying causes of narcolepsy, offering a comprehensive therapeutic approach.

The dual action of these molecules—enhancing neurotransmitter release and providing neuroinflammation protection—sets them apart from selective OX2R agonists, which have shown limitations such as receptor desensitization and reduced efficacy at higher doses. Our compounds, with their broader affinity, demonstrate a more stable pharmacological profile and promise better long-term outcomes.

This invention underscores Aexon Labs’ commitment to pioneering new therapeutic solutions that significantly improve the quality of life for individuals with narcolepsy and neurodegenerative diseases.

For more details, you can view the full patent application here WO2024115797.

Stay tuned for more updates as we continue to advance our research and bring these groundbreaking treatments closer to reality.

Non-Sulfonamide Orexin Receptor Agonists: A Safer Alternative

Introduction

A key differentiator of our compounds is their non-sulfonamide structure, which reduces the risk of side effects commonly associated with sulfonamide derivatives. This characteristic not only broadens their potential application but also enhances patient safety.

From Risk to Reliability

Given that the sulfonamide series is proven to be more potent than the amide series and displays negligible affinity for OX2R, it may seem counterintuitive to avoid developing sulfonamide-based orexin receptor agonists. However, the historical safety issues associated with sulfonamides necessitate a reevaluation of their long-term suitability for chronic conditions.

Lessons from the Past

Sulfonamides, while effective, have a notorious history, well-documented since the 1930s, of causing severe side effects. According to a comprehensive review published by the NIH, FDA Drug Safety Communications, and an extensive body of literature published in peer-reviewed journals, sulfonamide-induced adverse events such as hepatotoxicity (both hepatocellular and cholestatic injury) and hypersensitivity reactions (fever, rash, and eosinophilia) have been thoroughly documented.

Sulfonamide-based treatments for narcolepsy

In narcolepsy clinical trials, TAK-994, a methanesulfonamide derivative, encountered liver toxicity issues, leading to its discontinuation in phase 2. This was highlighted by Dauvilliers et al. (2023), who detailed the hepatotoxic risks associated with TAK-994. Similarly, other sulfonamide-based treatments have been linked to adverse effects such as hepatitis and severe allergic reactions, as increasingly reported. Beyond hepatotoxicity, cardiotoxicity, diuretic effects and ophthalmologic issues such as blurred vision or increased intraocular pressure, are other critical problems associated with a chronic administration of sulfonamide derivatives.

Advantages of Non-Sulfonamide Structures

Chronic conditions like narcolepsy require long-term treatment. The safer profile of non-sulfonamide dual orexin receptor agonists makes them more suitable for extended use, reducing the risk of cumulative adverse effects. The comprehensive action and improved safety profile lead to sustained therapeutic benefits and overall better patient outcomes and ensures better long-term compliance and efficacy. By leveraging the advantages of non-sulfonamide structures, Aexon Labs is committed to delivering innovative and safer therapeutic options for patients, setting a new standard in the treatment of narcolepsy and other related disorders.

Addressing Multiple Symptoms with Multi-Target Strategies

By targeting both orexin receptors (OX1R and OX2R) and integrating cathepsin inhibitors, our non-sulfonamide dual orexin receptor agonists provide a comprehensive solution that balances receptor activation and prevents desensitization, a common issue with high-affinity agonists. This multi-target strategy offers a well-rounded therapeutic approach, addressing the wide spectrum of symptoms associated with narcolepsy and improving overall patient outcomes.

Conclusion

The decision to develop non-sulfonamide orexin receptor agonists at Aexon Labs is grounded in a commitment to patient safety and therapeutic efficacy. While sulfonamide derivatives may offer potency, their long-term safety profiles make them unsuitable for chronic use. Our innovative approach, cultivated by historical insights and rigorous pharmacological evaluations, sets a new standard in the treatment of narcolepsy and related disorders. By leveraging the advantages of non-sulfonamide structures, Aexon Labs is committed to delivering innovative and safer therapeutic options for patients, setting a new standard in the treatment of narcolepsy and other related disorders.

Can Inhibiting Cathepsin H Unlock New Treatments for Narcolepsy?

Therapeutic Compounds Developed by Aexon Labs for Narcolepsy Aexon Labs is at the forefront of developing innovative therapeutic compounds targeting neurodegenerative disorders, including narcolepsy. Their focus is on addressing the root causes of these conditions by leveraging expertise in orexin receptor pathways and cathepsin H (CTSH) inhibition.

Historical Aspects and New Insights Narcolepsy has been studied extensively since its initial description by Jean-Baptiste Gélineau (in 1880) and further by Jean Lhermitte (in 1910). Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. The discovery (in 1998) that narcolepsy is caused by the loss of hypocretin (orexin)-producing neurons in the lateral hypothalamus was a significant breakthrough. More recent evidence strongly suggests an autoimmune basis for narcolepsy, with a strong association with HLA DQB1*06:02. Genome-wide association studies have identified immune system gene polymorphisms linked to narcolepsy, including variations in the T cell receptor alpha locus, TNFSF4 (OX40L), CTSH, the purinergic receptor P2RY11, and DNA methyltransferase DNMT1.

Pathophysiological Hypothesis The pathophysiology of narcolepsy involves an autoimmune component characterized by genetic predisposition marked by HLA-DQB1*06:02 and other immune-related polymorphisms. T cells specifically target hypocretin-producing neurons, potentially through molecular mimicry where T cells activated by infections or vaccinations cross-react with hypocretin neurons. Neuroinflammation, driven by increased levels of pro-inflammatory cytokines such as IL-17 and IFN-γ, plays a significant role in the disease progression, leading to the destruction of orexin neurons. CTSH is involved in the proteolytic degradation of cellular proteins and has high expression in antigen-presenting cells, playing a role in MHC II-peptide interactions. Alterations in CTSH activity can influence the antigenic profile presented to T cells, exacerbating the autoimmune response. Data from the STRING database demonstrated significant interactions between CTSH, orexin (HCRT), and HLA-DRB1, supporting that proteins involved in immune response and cellular stress pathways are linked to narcolepsy, and CTSH might play a role through these pathways. CTSH interacts with other proteins that are part of immune system processes, potentially influencing the development of narcolepsy (STRING Database link).

Potential Therapeutic Implications Therapeutic strategies that inhibit CTSH could disrupt the proteolytic pathway, potentially protecting neuronal cells. When combined with agonist action on OX1R and OX2R receptors, this approach could significantly enhance orexin signaling stability and mitigate symptoms. Neuroprotective strategies focusing on reducing neuroinflammation and modulating immune responses could further improve therapeutic outcomes.

Recent Advances and Presentations At the ASCP Annual Meeting 2024, Aexon Labs presented groundbreaking data on their dual orexin receptor agonists and CTSH inhibitors. The presentation highlighted the dual mechanism of action of these compounds, showcasing their potential to improve wakefulness and reduce cataplexy while addressing underlying autoimmune mechanisms. Preliminary clinical data indicated promising results in terms of safety and efficacy, setting the stage for further clinical trials scheduled for later in the year.

Conclusion Aexon Labs’ innovative compounds, particularly their dual orexin receptor agonists with CTSH inhibitory action, represent a promising advancement in the treatment of narcolepsy. By addressing both symptomatic relief and underlying autoimmune mechanisms, these therapies have the potential to significantly improve the quality of life for individuals with narcolepsy.

References

Mahlios, E., et al. (2013). The autoimmune basis of narcolepsy. Current Opinion in Neurobiology, 23(5), 767-773. Link
Wurts Black, S., et al. (2017). Challenges in the development of therapeutics for narcolepsy. Progress in Neurobiology, 152, 89-113. Link
Szabo, A., et al. (2019). Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy. Sleep Medicine Reviews, 43, 23-36. Link
Konofal, E. (2024). From Past to Future: 50 years of Pharmacological Interventions to Treat Narcolepsy. Pharmacology, Biochemistry and Behavior (Available online 7 June 2024, 173804) Link