Steering Toward Breakthroughs: CRISPR-Cas9, the Nobel Prize-Winning Genetic Marvel by Jennifer Doudna and Emmanuelle Charpentier, Nears its Debut in Alzheimer’s Clinical Trials. Yet, Amidst the Excitement, Lingering Hurdles and the Need for Caution Spark Intrigue.
A Spark of Innovation in Amsterdam: Unveiling at the Alzheimer’s Association International Conference (AAIC), Visionary Minds from UC San Diego and Duke University School of Medicine Showcase Dual CRISPR Breakthroughs Against Alzheimer’s, Paving the Path to Prevention and Cure.
Unleashing CRISPR Magic at UC San Diego: Meet Brent Aulston and His Team Rewriting the Story of Alzheimer’s by Editing the Amyloid Precursor Protein (APP). This Mighty Protein, Nestled in Neuronal Synapses and Beyond, Holds the Key to Transformation.
Unveiling Secrets at the Genetic Frontier: As Revealed by Brent Aulston to BioSpace, the Intriguing Link Between Alzheimer’s and Genetic Variants Lies in the Enigmatic Dance of APP. This Dance, Orchestrated by Mysterious Enzymes, Holds the Clues to Unraveling the Alzheimer’s Enigma.
Unraveling the Intrigue of Enzyme Symphony: Meet the Star Performer, Alpha Secretase! Imagine a Molecular Waltz Within Our Cells, Where APP Takes the Lead Role. With a Graceful Swirl, Alpha Secretase Steps In, Unveiling the Protector, Secreted APP-Alpha—a Guardian Angel Molecule. But Alas, in the Drama of Alzheimer’s, Beta-Secretase Makes an Entrance, Leading APP Down a Mysterious Pathway. This Dark Journey Gives Birth to the Infamous Villains of the Story: Amyloid-Beta Peptides, the Sinister Fragments of the Mind.
Crafting a Genetic Symphony with CRISPR Brushes: Aulston’s Genius Squad Takes the Stage! Behold, the Ambitious Plan: Rewriting the APP Gene, Morphing the Dance Steps. Their Aim? More Elegance in Alpha Cuts, Less Drama in Beta. The Quest for Balance, Where Genetic Manipulation Unveils a New Chapter in the Alzheimer’s Saga.
Whispering to Nature’s Blueprint: Aulston’s Clarion Call Rings Clear! In the Enchanted Realm of Genes, Precision is Key. Behold, the Goal: Not to Silence the APP Symphony Entirely, But to Tune it Anew. Like a Conductor Orchestrating Cosmic Notes, Aulston Ensures the Brain’s Concerto Remains Undisturbed. Imagine, a Mouse Without APP is a World Amiss—Shrunken, Clouded, and Diminished. Let the Dance of Proteins Persist, Let the Melody of Mind Flourish!
Crafting Nature’s Edits with CRISPR’s Quill: Behold, the Masters of Design! In the Laboratory Theater, a Bold Stroke: Edit Just a Glimpse of APP’s Script, All to Shield it from Beta-Secretase’s Touch. Like Cosmic Architects, They Whisper Changes, Guiding Proteins Through a New Choreography. A Glimpse of the Test Stage Reveals Mice in a Dance of Transformation—Less Amyloid-Beta Curtains, More Neuroprotective APP Stars, and an Orchestra of Diminished Brain Inflammation Markers.
Unveiling a Symphony of Possibilities: Aulston’s Revelation Shatters Boundaries! Imagine, Retaining the Heartbeat of APP’s Functions, While Breathing Life into Secreted APP-Alpha’s Growth—A Marvelous Transformation! As the Curtain Rises, Mice Take Center Stage, Their Behavior and Minds Alight with Improvement. A Whispered Promise Echoes in Abstracts of Brilliance at AAIC: Our Strategy, Safe and Potent, Beckons Human Testing’s Threshold. The Quest Continues, as We Dance Closer to Unveiling the Enigma of Alzheimer’s.
Stepping onto the Neurological Stage: Meet the Maestro of Doubt, Rudolph “Rudy” Tanzi! Amidst the Whispers of CRISPR’s Promise, a Note of Caution Springs Forth. In a Harmonious Conversation with BioSpace, Tanzi Paints APP as an Enigmatic Muse. “APP: All-Purpose Protein,” He Chuckles, as the Multifaceted Marvel Dances Through Neuronal Chronicles. Synapses Find a Sturdy Embrace, Blood’s Clotting Tale Unfolds—A Virtuoso of Roles. With a Glimpse of Skepticism, Tanzi Raises an Ovation of Inquiry.
Duke Targets APOE
Scientists at Duke University School of Medicine are using CRISPR-Cas9 gene editing to target the APOE ε4 gene, which is associated with an increased risk of Alzheimer’s disease. The APOE ε4 allele is carried by an estimated 15-25% of the population, and up to 5% of people have two copies of the gene.
Dr. Ornit Chiba-Falek, a professor of neurology at Duke University, is leading a team of researchers who are developing a new way to prevent Alzheimer’s disease. The team is targeting the APOE ε4 gene, which is associated with an increased risk of the disease.
A new study presented at the Alzheimer’s Association International Conference (AAIC) shows that CRISPR-Cas9 gene editing can be used to efficiently and precisely edit the APOE ε4 gene in miniature brains derived from human induced pluripotent stem cells (hiPSCs) from an Alzheimer’s patient and in humanized mouse models.
Dr. Ornit Chiba-Falek and Boris Kantor, associate research professor of neurobiology at Duke University, have co-founded a biotech company called CLAIRIgene to further develop a CRISPR-Cas9 gene editing platform that could be used to prevent Alzheimer’s disease.
Tough Translational Terrain
Dr. Aulston and his team have successfully proven the concept of editing the APP gene in mice, which could potentially lead to a new treatment for Alzheimer’s disease. However, they know that the human brain is much more complex than a mouse’s brain, and they will need to overcome many challenges before their research can be translated into a clinical treatment.
Gerold Schmitt-Ulms, a professor at the University of Toronto studying Alzheimer’s, tauopathies, and prion disorders, is concerned about the translatability of CRISPR gene editing to neurological diseases. He told BioSpace that the technology is “lagging behind” other gene therapy approaches in this space for two main reasons: immunogenicity and delivery challenges.
AAV capsids are a type of virus that is commonly used to deliver gene therapy to cells. However, around 70% of people have been exposed to natural AAVs and therefore carry antibodies in their blood that would destroy AAV-based gene therapy vectors. This means that the body’s immune system can attack the AAV capsids, preventing them from delivering the CRISPR machinery to the target cells.
Most current gene therapy clinical trials for neurodegenerative diseases involve the delivery of a particular overexpressed protein. This is because the body is already familiar with these proteins, so they are less likely to trigger an immune response.
As Gerold Schmitt-Ulms, a professor at the University of Toronto studying Alzheimer’s, tauopathies, and prion disorders, said, “To date, no one can deliver any of these gene therapies to every cell in the human brain.” The best one can currently achieve is that a few percent of the brain cells take up the therapeutic virus. Often, that is not enough for the desired benefit to manifest.”
The APOE ε4 gene is a risk factor for Alzheimer’s disease. People who carry two copies of the gene are at a much higher risk of developing the disease than those who do not carry the gene.
Dr. Rudolph Tanzi, a professor of neurology at Harvard University, is concerned about the rapid pace of development of CRISPR gene editing. He compares the genome to the ocean, saying that we should respect and live with it, but that we should not take it for granted.
“Once you think you know it, it can take you out,” he said.