COMPOSITION AND METHOD FOR THE TREATMENT OF ALZHEIMER'S DISEASE USING SMALL MOLECULE INHIBITORS

Abstract

COMPOSITION AND METHOD FOR THE TREATMENT OF ALZHEIMER'S DISEASE USING SMALL MOLECULE INHIBITORS ABSTRACT The invention relates to a composition and method for the treatment of Alzheimer's disease using small molecule inhibitors. The composition targets the aggregation of beta-amyloid plaques and tau proteins, which are central to Alzheimer’s pathology. The method involves administering the composition to reduce amyloid-beta production, tau hyperphosphorylation, and neuroinflammation. The inhibitors are formulated for enhanced bioavailability, allowing effective blood-brain barrier penetration. The treatment provides both symptomatic relief and disease-modifying effects, offering a comprehensive approach to Alzheimer’s therapy by slowing neurodegeneration and improving cognitive function.

Specification

Description:COMPOSITION AND METHOD FOR THE TREATMENT OF ALZHEIMER'S DISEASE USING SMALL MOLECULE INHIBITORS

FIELD OF THE INVENTION

The present invention relates to a composition and method for the treatment of Alzheimer's disease using small molecule inhibitors. Specifically, the invention focuses on the development and use of novel small molecule inhibitors targeting key proteins involved in the pathogenesis of Alzheimer's disease, such as beta-amyloid and tau proteins, which are known to aggregate and lead to neurodegeneration. The invention addresses both therapeutic intervention and disease modification through the inhibition of pathways that contribute to cognitive decline in Alzheimer's patients.
BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the elderly population, leading to memory loss, cognitive impairment, and ultimately death. The accumulation of beta-amyloid plaques and tau tangles in the brain are the hallmarks of the disease. These aggregates disrupt neuronal function, leading to cell death and the associated clinical symptoms of AD. Current treatments for Alzheimer's provide symptomatic relief but fail to address the underlying pathology of the disease.
Several therapeutic approaches have been explored, including monoclonal antibodies and gene therapy, but these have encountered significant challenges in clinical translation due to poor blood-brain barrier penetration, high cost, and variable efficacy. Small molecule inhibitors, due to their smaller size, have emerged as promising candidates for Alzheimer's treatment. They offer advantages such as better bioavailability, easier synthesis, and the potential to directly interfere with key disease-related proteins.
However, no small molecule inhibitors currently available provide both disease-modifying and symptomatic benefits. This invention focuses on developing a composition that targets multiple pathways involved in Alzheimer's pathology, including amyloid-beta production, tau hyperphosphorylation, and neuroinflammation, by employing novel small molecule inhibitors designed for better blood-brain barrier penetration and targeted efficacy.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a novel composition comprising small molecule inhibitors for the treatment of Alzheimer's disease. These small molecules are specifically designed to inhibit the aggregation of beta-amyloid plaques and tau proteins. In one embodiment, the composition includes a synergistic combination of inhibitors targeting both amyloidogenic and tauopathies, thereby addressing the multifactorial nature of the disease.
In an embodiment, the method involves administering the composition to patients diagnosed with Alzheimer's disease or at risk of developing it. The small molecule inhibitors work by disrupting the amyloid-beta aggregation process, reducing tau phosphorylation, and inhibiting neuroinflammation pathways. This treatment is aimed at not only alleviating the symptoms of Alzheimer's disease but also modifying its progression by halting or slowing neurodegenerative processes.
In another embodiment, the invention focuses on enhancing the bioavailability of the small molecule inhibitors, ensuring they cross the blood-brain barrier effectively. Formulation techniques are employed to improve solubility and stability, allowing for effective delivery to target sites in the brain. This novel approach ensures better patient outcomes by reducing neurotoxic effects associated with Alzheimer's pathology.


BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures where like reference numerals refer to identical or functionally similar elements throughout the separate views and which together with the detailed description below are incorporated in and form part of the specification, serve to further illustrate various embodiments and to explain various principles and advantages all in accordance with the invention.
The accompanying figure illustrates the method of treating Alzheimer's disease using the composition of small molecule inhibitors. The figure highlights the mechanism of action, including the inhibition of beta-amyloid plaque formation, tau hyperphosphorylation, and neuroinflammation. The figure also demonstrates the pathways targeted by the inhibitors and the delivery system used to ensure effective penetration of the blood-brain barrier.
Skilled artisans will appreciate the elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of embodiments of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed. It shall be understood that different aspects of the invention can be appreciated individually, collectively, or in combination with each other.
In an embodiment, the invention provides a composition comprising small molecule inhibitors that target the amyloidogenic and tauopathic pathways. One such small molecule inhibits the enzyme β-secretase (BACE1), preventing the production of amyloid-beta from amyloid precursor protein (APP). Another small molecule inhibits the activity of glycogen synthase kinase-3 (GSK-3), which is responsible for tau hyperphosphorylation. Together, these molecules reduce the aggregation of amyloid plaques and tau tangles in the brain.
In another embodiment, the composition includes an inhibitor of the receptor for advanced glycation end products (RAGE), which has been implicated in neuroinflammation and cognitive decline in Alzheimer's disease. The inclusion of this inhibitor reduces neuroinflammatory responses and protects neurons from further damage.
The method of administration involves oral delivery of the composition, designed to ensure optimal bioavailability. The small molecule inhibitors are formulated with nanoparticles or liposomes to enhance their solubility and allow for efficient crossing of the blood-brain barrier. In an embodiment, the composition is administered once daily, with dosages adjusted based on the severity of the disease and patient response.
In another embodiment, the method of treatment may also be combined with existing Alzheimer's therapies such as acetylcholinesterase inhibitors or NMDA receptor antagonists. The synergistic effect of these combined treatments can enhance cognitive function while the small molecule inhibitors work to slow the progression of the disease.
Clinical studies have demonstrated the efficacy of the composition in reducing the burden of beta-amyloid and tau aggregates in preclinical models of Alzheimer's disease. These findings suggest a significant reduction in cognitive decline and improved neuronal health in patients treated with the composition.
Furthermore, the composition is shown to reduce oxidative stress in neurons, which is a critical factor in the progression of Alzheimer's disease. By targeting both amyloidogenic and tauopathic pathways, the invention offers a comprehensive approach to treating Alzheimer's disease.
Advantages of the Invention
1. Targeted Action: The small molecule inhibitors are designed to specifically target beta-amyloid and tau pathways, offering disease-modifying effects and reducing neurodegeneration.
2. Improved Bioavailability: The use of formulation techniques such as nanoparticles ensures that the inhibitors can effectively cross the blood-brain barrier, providing enhanced therapeutic efficacy.
3. Comprehensive Treatment: The composition addresses multiple pathological processes, including amyloid-beta aggregation, tau hyperphosphorylation, and neuroinflammation, offering a holistic approach to Alzheimer's treatment.
4. Cost-Effective: Small molecule inhibitors are generally easier to manufacture and more affordable than biological therapies like monoclonal antibodies, making them accessible to a larger patient population.
5. Symptomatic and Disease-Modifying: The composition not only alleviates symptoms but also targets the underlying causes of Alzheimer's disease, slowing down disease progression.
Embodiment 1: Inhibition of Beta-Amyloid Plaque Formation
In an embodiment, the composition includes a small molecule inhibitor targeting β-secretase (BACE1), an enzyme that cleaves amyloid precursor protein (APP) into amyloid-beta peptides. Amyloid-beta accumulation is a primary factor in Alzheimer's disease, leading to the formation of extracellular plaques that disrupt neuronal communication. The small molecule inhibitor in this embodiment binds to the active site of BACE1, preventing its interaction with APP, thereby reducing the production of amyloid-beta.
The inhibitor is designed with a high affinity for BACE1 and optimized for blood-brain barrier penetration. In preclinical studies, this inhibitor showed a significant decrease in amyloid-beta levels in animal models of Alzheimer's, resulting in improved cognitive performance. This embodiment focuses on preventing the formation of toxic plaques, a key driver of neurodegeneration in Alzheimer's disease.
Embodiment 2: Reduction of Tau Hyperphosphorylation
In another embodiment, the invention targets tau protein hyperphosphorylation by inhibiting glycogen synthase kinase-3 (GSK-3). GSK-3 is a key enzyme involved in the abnormal phosphorylation of tau proteins, which leads to the formation of neurofibrillary tangles, a hallmark of Alzheimer's disease. The small molecule inhibitor in this embodiment selectively inhibits GSK-3, preventing the phosphorylation of tau proteins and thereby reducing the formation of intracellular tangles.
This embodiment can be used in conjunction with the β-secretase inhibitor to provide a dual mechanism of action, tackling both amyloid and tau pathologies simultaneously. Clinical results from preclinical models demonstrate that inhibiting GSK-3 reduces tau aggregates and preserves neuronal structure, leading to better cognitive outcomes for patients.
Embodiment 3: Inhibition of Neuroinflammation
In an embodiment, the composition includes a small molecule inhibitor targeting the receptor for advanced glycation end products (RAGE). RAGE is implicated in neuroinflammation and cognitive impairment in Alzheimer's disease by binding to amyloid-beta peptides and triggering inflammatory responses in neurons. This embodiment focuses on reducing neuroinflammation, which exacerbates the progression of Alzheimer's disease.
The RAGE inhibitor used in this embodiment blocks the interaction between amyloid-beta and RAGE, thereby preventing the activation of downstream inflammatory pathways. By reducing neuroinflammation, this embodiment aims to protect neurons from further damage and slow the progression of cognitive decline.
Embodiment 4: Formulation for Enhanced Bioavailability
In an embodiment, the small molecule inhibitors are formulated with nanoparticles to enhance their solubility and stability, ensuring effective delivery across the blood-brain barrier. The nanoparticles are designed to encapsulate the small molecule inhibitors, protecting them from degradation in the gastrointestinal tract and allowing for controlled release at the target site in the brain.
This embodiment significantly improves the bioavailability of the small molecule inhibitors, ensuring that therapeutic concentrations are achieved within the central nervous system. The formulation has been optimized for oral administration, making it suitable for long-term treatment regimens.
Embodiment 5: Combination Therapy with Existing Alzheimer's Treatments
In another embodiment, the small molecule inhibitors are used in combination with existing Alzheimer's treatments, such as acetylcholinesterase inhibitors or NMDA receptor antagonists. Acetylcholinesterase inhibitors enhance cholinergic transmission in the brain, providing symptomatic relief, while NMDA receptor antagonists prevent excitotoxicity caused by excessive glutamate signaling.

This embodiment leverages the benefits of existing therapies while introducing a disease-modifying component with the small molecule inhibitors. By targeting both symptom relief and the underlying pathology, this combination therapy offers a more comprehensive treatment strategy for Alzheimer's disease.
Embodiment 6: Customized Dosage and Treatment Plan
In an embodiment, the method of treatment involves a customized dosage plan based on the severity of Alzheimer's disease in the patient. The dosage of small molecule inhibitors can be adjusted according to the stage of the disease, with higher doses administered in early stages to prevent plaque and tangle formation, and maintenance doses in later stages to preserve cognitive function and reduce neurodegeneration.
This embodiment ensures personalized treatment, optimizing the efficacy of the composition for different patient populations and disease stages.
Embodiment 7: Early Intervention for High-Risk Patients
In an embodiment, the composition and method are used for early intervention in patients at high risk of developing Alzheimer's disease, such as those with a family history or genetic markers like the APOE ε4 allele. Administering the small molecule inhibitors before the onset of clinical symptoms can reduce the accumulation of amyloid-beta and tau aggregates, delaying the onset of Alzheimer's disease and preserving cognitive function for a longer period.
This preventive approach offers significant potential for reducing the overall burden of Alzheimer's disease in at-risk populations.
Embodiment 8: Neuroprotective Effects Through Antioxidant Mechanisms
In another embodiment, the composition not only targets amyloid-beta and tau but also provides neuroprotection by reducing oxidative stress in neurons. Alzheimer's disease is associated with increased levels of oxidative damage in the brain, which contributes to neurodegeneration. The small molecule inhibitors in this embodiment include antioxidant properties, scavenging free radicals and reducing oxidative damage in neurons.

This embodiment offers additional neuroprotective benefits, preserving neuronal health and reducing the progression of Alzheimer's disease.
Embodiment 9: Improved Cognitive Function and Memory Retention
In an embodiment, the administration of the composition results in improved cognitive function and memory retention in patients with Alzheimer's disease. Clinical studies using animal models show that the composition improves performance in memory-based tasks, such as maze navigation, and reduces behavioral symptoms associated with cognitive decline.
, Claims:I/WE CLAIM:
1. A method for treating Alzheimer's disease in a patient comprising administering a composition comprising small molecule inhibitors that target beta-amyloid and tau protein aggregation.
2. The method of claim 1, wherein the small molecule inhibitors include a β-secretase inhibitor that reduces the production of amyloid-beta.
3. The method of claim 1, wherein the small molecule inhibitors include a glycogen synthase kinase-3 inhibitor that reduces tau protein hyperphosphorylation.
4. The method of claim 1, wherein the composition includes an inhibitor of the receptor for advanced glycation end products (RAGE) to reduce neuroinflammation.
5. The method of claim 1, wherein the composition is administered orally.
6. The method of claim 1, wherein the composition is formulated with nanoparticles for enhanced bioavailability.
7. The method of claim 1, wherein the treatment reduces the cognitive decline associated with Alzheimer's disease.
8. The method of claim 1, wherein the composition is administered in combination with acetylcholinesterase inhibitors or NMDA receptor antagonists.
9. The method of claim 1, wherein the composition reduces oxidative stress in neurons.

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