Advancing Alzheimer’s Research with Stable Beta-Amyloid Oligomers

Introduction

Neurodegenerative diseases, particularly Alzheimer’s, represent a significant challenge in modern medicine. One of the key factors in these diseases is the accumulation of beta-amyloid plaques in the brain, a process driven by amyloid oligomers. While much research has focused on these plaques, targeting oligomers directly could offer a new therapeutic pathway. Our patented synthetic beta-amyloid peptides capable of forming stable antigenic oligomers open new doors for Alzheimer’s research, diagnostics, and treatment, offering a highly targeted approach to managing amyloid aggregation disorders.

The Urgent Need for Innovative Alzheimer’s Treatments

Alzheimer’s disease remains one of the most complex and devastating neurodegenerative conditions, affecting millions of people worldwide. Current treatments focus on symptom management rather than addressing the underlying cause of the disease—namely, the misfolding and aggregation of beta-amyloid peptides into toxic oligomers and plaques. Despite decades of research, there is still no cure, and effective therapies are limited.

Researchers and pharmaceutical companies face the challenge of developing treatments that can slow or stop disease progression by targeting these amyloid oligomers, which are believed to be more toxic than the plaques themselves. Additionally, developing diagnostic tools to detect these oligomers early could drastically improve patient outcomes by enabling earlier intervention.

Targeting Beta-Amyloid Oligomers with Stability and Precision

Our patented synthetic beta-amyloid peptides offer a breakthrough in this area by forming stable antigenic oligomers that closely mimic the toxic species found in neurodegenerative diseases like Alzheimer’s. These peptides can be used as a model for studying the mechanisms of amyloid aggregation and provide a critical tool for developing diagnostics, vaccines, and treatments. The stable nature of these oligomers makes them ideal for drug screening, allowing researchers to test compounds that could inhibit amyloid formation or enhance clearance from the brain.

Furthermore, these synthetic oligomers can be used in diagnostic assays to detect early amyloid aggregation, enabling the development of blood tests or other non-invasive methods for diagnosing Alzheimer’s before symptoms fully develop. This could significantly enhance early intervention strategies.

Key Benefits

Therapeutic Development: Enables the creation of drugs and vaccines targeting toxic amyloid oligomers in Alzheimer’s and related diseases.
Stable and Reproducible: Provides a reliable model for studying amyloid aggregation and testing potential inhibitors.
Diagnostic Potential: Can be used in diagnostic assays to detect amyloid aggregation early, improving the chances of early intervention.
Broad Application: Valuable for research, drug discovery, and diagnostics related to neurodegenerative diseases.

A New Avenue for Alzheimer’s Research and Treatment

Licensing this synthetic beta-amyloid peptide technology provides pharmaceutical companies and research institutions with a powerful tool to accelerate the development of new diagnostics and therapies for Alzheimer’s disease. This technology represents a key advance in targeting the toxic oligomers that drive neurodegeneration.

Please see terms and conditions

Abstract
Claims

Synthetic Aβ peptides, oligomers, their methods of synthesis, and their applications are provided. The Aβ peptides can form stable, soluble oligomers important for the advancement of knowledge, detection, and treatment of Alzheimer’s disease. Antibodies specific to oligomeric Aβ and their methods of synthesis are also described.

What is claimed is:

1. A method of producing antibodies having affinity for soluble beta-amyloid oligomers comprising:

administering to an immunocompetent animal with an immunogenic cocktail comprising a synthetic beta-amyloid trimer;

wherein the beta-amyloid trimer is a trimer selected from the group consisting of:

a trimer having a first, a second, and a third synthetic beta-amyloid peptide, each peptide comprises Seq. ID No. 3 or a substantially similar sequence;

wherein the cysteine in amino acid position two of the first peptide forms a disulfide linkage with the cysteine in amino acid position six of the second peptide;

wherein the cysteine in amino acid position two of the second peptide forms a disulfide linkage with the cysteine in amino acid position six of the third peptide;

wherein the cysteine in amino acid position two of the third peptide forms a disulfide linkage with the cysteine in amino acid position six of the first peptide; and

wherein the substantially similar sequence consists of an addition, a removal, or a substitution of up to three amino acids yet maintains each cysteine amino acid of the peptide in its identified position;

a trimer having a first, a second, and a third synthetic beta-amyloid peptide, each peptide comprises Seq. ID No. 4 or a substantially similar sequence;

wherein the cysteine in amino acid position fifteen of the first peptide forms a disulfide linkage with the cysteine in amino acid position nineteen of the second peptide;

wherein the cysteine in amino acid position fifteen of the second peptide forms a disulfide linkage with the cysteine in amino acid position nineteen of the third peptide;

wherein the cysteine in amino acid position fifteen of the third peptide forms a disulfide linkage with the cysteine in amino acid position nineteen of the first peptide; and

a trimer having a first, a second, and a third synthetic beta-amyloid peptide, each peptide consists of a first and a second strand, the first strand comprises Seq. ID No. 5 or a substantially similar sequence, and the second strand comprises Seq. ID No. 6 or a substantially similar sequence;

wherein the first and second strand are covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the first strand to the C-terminus of the second strand, and

wherein the first and second strand are also covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the second strand to the C-terminus of the first strand;

wherein the cysteine in amino acid position two of the first strand of the first peptide forms a disulfide linkage with the cysteine in amino acid position six of the first strand of the second peptide;

wherein the cysteine in amino acid position two of the first strand of the second peptide forms a disulfide linkage with the cysteine in amino acid position six of the first strand of the third peptide;

wherein the cysteine in amino acid position two of the first strand of the third peptide forms a disulfide linkage with the cysteine in amino acid position six of the first strand of the first peptide; and

wherein any of the substantially similar sequences is a sequence that allows consists of an addition, a removal, or a substitution of up to three amino acids yet maintains each cysteine amino acid of the peptide its identified position; and

a trimer having a first, a second, and a third synthetic beta-amyloid peptide, each peptide consists of a first and a second strand, the first strand comprises Seq. ID No. 7 or a substantially similar sequence, and the second strand comprises Seq. ID No. 8 or a substantially similar sequence;

wherein the first and second strand are covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the first strand to the C-terminus of the second strand, and

wherein the first and second strand are also covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the second strand to the C-terminus of the first strand;

wherein the cysteine in amino acid position two of the second strand of the first peptide forms a disulfide linkage with the cysteine in amino acid position six of the second strand of the second peptide;

wherein the cysteine in amino acid position two of the second strand of the second peptide forms a disulfide linkage with the cysteine in amino acid position six of the second strand of the third peptide;

wherein the cysteine in amino acid position two of the second strand of the third peptide forms a disulfide linkage with the cysteine in amino acid position six of the second strand of the first peptide; and

2. The method of claim 1, wherein at least one synthetic beta-amyloid peptide incorporates an ornithine in the amino acid position that corresponds to methionine35 of a naturally occurring beta-amyloid peptide.

3. The method of claim 1, wherein at least one central amino acid is N-methylated.

4. The method of claim 1, wherein the synthetic beta-amyloid peptide has at least one amino acid mutation that corresponds to familial Alzheimer’s disease.

5. The method of claim 1, wherein any of the substantially similar sequences is a sequence that allows consists of an addition, a removal, or a substitution of up to two amino acids but still maintains each cysteine amino acid of the peptide in its identified position.

6. The method of claim 1, wherein any of the substantially similar sequences is a sequence that allows consists of an addition, a removal, or a substitution of one amino acids but still maintains each cysteine amino acid of the peptide in its identified position.

7. The method of claim 1, wherein any of the substantially similar sequences is an identical sequence that does not have an addition, a removal, or a substitution of an amino acid.

8. The method of claim 1 further comprising: harvesting antibodies from the immunocompetent animal.

9. The method of producing antibodies of claim 1 further comprising repeating administration of beta-amyloid trimers to the immunocompetent animal.

10. The method of claim 1, wherein the immunocompetent animal is selected from the group consisting of human, rabbit, goat, mouse, rat, chicken, and guinea pig.

11. The method of claim 1, wherein the immunogenic cocktail further comprises an adjuvant.

12. The method of claim 1, wherein the adjuvant is Freund’s adjuvant.

13. The method of claim 1, wherein the at least one beta-amyloid trimer is conjugated with hemocyanin.

14. The method of claim 1, wherein the immunocompetent animal is a human individual for the purpose of vaccination.

Title

Synthetic beta-amyloid peptides capable of forming stable antigenic oligomers

Inventor(s)

James S. Nowick, Adam G. Kreutzer, Ryan K. Spencer, Patrick J. Salveson

Assignee(s)

University of California

Patent #

11319348

Patent Date

May 3, 2022