A significant announcement from biotech company Aperture Therapeutics is sending waves of hope through the dementia research community.
The company has nominated a new development candidate, APRTX-001, a precision-engineered drug designed to tackle the neuroinflammation that drives devastating neurodegenerative diseases like Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS), with a hopeful eye toward Alzheimer’s disease.
For anyone whose life has been touched by dementia, this news represents a critical step forward in the quest for effective treatments.
This article will break down this complex scientific development, exploring what it means for the fight against dementia and why this approach is generating so much excitement.
Understanding the Landscape: FTD and the Role of Brain Inflammation
Frontotemporal Dementia, or FTD, is a group of brain disorders that primarily affect the frontal and temporal lobes of the brain—areas responsible for personality, behavior, and language [1].
It is the second most common cause of early-onset dementia, typically striking between the ages of 40 and 65, and accounts for an estimated 10-20% of all dementia cases [2].
Unlike Alzheimer’s disease, which is often characterized by initial memory loss, FTD’s early symptoms are typically marked by drastic changes in personality and behavior or a progressive loss of language skills [1].
At the heart of many neurodegenerative diseases, including FTD and Alzheimer’s, is a destructive process called neuroinflammation. Our brains have specialized immune cells called microglia, which act as housekeepers, clearing away cellular debris and toxic proteins.
In a healthy brain, these cells maintain a delicate balance, known as homeostasis. However, in neurodegenerative conditions, microglia can become dysfunctional. Instead of cleaning up, they can turn into pro-inflammatory cells, contributing to a state of chronic inflammation that damages and kills neurons, accelerating the progression of the disease [3].
The Culprit: What is the CD33 Protein?
Recent genetic research has identified a key player in this inflammatory process: a protein called CD33. The CD33 gene has been confirmed as a significant risk factor for late-onset Alzheimer’s disease [4].
In the brain, CD33 is found on the surface of microglia, where it acts as a brake, suppressing their ability to perform their cleanup duties. Studies have shown that higher levels of CD33 on microglia inhibit their capacity to clear away amyloid-beta, the toxic protein that forms plaques in the brains of Alzheimer’s patients [4].
Crucially, elevated CD33 expression isn’t just a feature of Alzheimer’s. It is consistently found in the brain tissue of patients with FTD, ALS, and Parkinson’s disease, highlighting its central role in the microglial dysfunction that underpins these devastating conditions.
Conversely, scientists have observed that individuals with a naturally occurring genetic variant that reduces CD33 levels show increased resilience to neurodegenerative diseases, reduced neuroinflammation, and lower levels of disease-related biomarkers [5].
This discovery provided a clear therapeutic target: if you can reduce or inhibit CD33, you might be able to restore the microglia’s healthy function and slow down the disease.
A Precision Strike: How APRTX-001 Works
Targeting CD33 has been a goal for researchers for some time, but previous attempts using traditional drug types like small molecules and antibodies have been unsuccessful. This is where Aperture Therapeutics’ approach with APRTX-001 is so innovative.
APRTX-001 is an antisense oligonucleotide (ASO), a type of therapy that can be designed to precisely target the genetic instructions for making a specific protein.
Think of it like this: if the CD33 gene is the blueprint for the problematic protein, the RNA is the instruction manual sent to the cell’s protein-making machinery. An ASO is a synthetic piece of genetic material that intercepts and neutralizes that specific instruction manual before the protein can even be built.
By directly modulating CD33 at the RNA level, APRTX-001 aims to replicate the protective effects of the beneficial low-CD33 genetic variants, effectively “releasing the brakes” on microglia and allowing them to resume their vital housekeeping functions.
“Although CD33 has long been recognized as an important regulator of neuroinflammation in neurodegenerative disease, prior attempts to drug this pathway… have failed,” said Dr. Martin Jacko, Founder and CEO of Aperture Therapeutics. “By directly modulating CD33 at the RNA level, APRTX-001 overcomes these historical barriers with a precision approach grounded in human genetics.” [5]
ASO therapies are already approved for treating other neurological conditions, such as spinal muscular atrophy, and are being actively investigated for Huntington’s disease, ALS, and Alzheimer’s, making this a rapidly advancing and promising field of medicine [6].
What This Breakthrough Means for the Dementia Community
While APRTX-001 is currently focused on FTD and ALS, the implications for the broader dementia community are profound. Here are the key takeaways:
| Implication | Description |
|---|---|
| A New Therapeutic Avenue | This research validates targeting neuroinflammation and microglial function as a viable strategy for treating dementia, moving beyond a singular focus on amyloid plaques. |
| Potential for Alzheimer’s | Given that CD33 is a major risk factor for Alzheimer’s, the successful development of APRTX-001 could pave the way for its use in treating the most common form of dementia. |
| Precision Medicine | The ASO approach represents a new wave of precision medicine for brain diseases, offering a way to target the root genetic causes of disease with high specificity. |
| Hope for FTD | For a disease with no cure and limited treatment options, the advancement of a genetically-informed, first-in-class therapeutic candidate is a major beacon of hope. |
It is important to maintain a realistic perspective. APRTX-001 is currently in the preclinical phase, meaning it is undergoing the necessary laboratory and animal model testing before it can be considered for human clinical trials.
This journey is long and rigorous. However, the nomination of a development candidate is a significant milestone, marking the transition from pure research to a tangible therapeutic program.
This news from Aperture Therapeutics is a powerful reminder that progress is being made. By targeting the fundamental mechanisms of neuroinflammation, scientists are opening up new and exciting fronts in the war against dementia.
For the millions of individuals and families affected, every step forward, no matter how early, brings renewed hope for a future free from these devastating diseases.
References
[1] Mayo Clinic. “Frontotemporal dementia – Symptoms and causes.” https://www.mayoclinic.org/diseases-conditions/frontotemporal-dementia/symptoms-causes/syc-20354737
[2] The AFTD. “Fast Facts about Frontotemporal Degeneration.” https://www.theaftd.org/wp-content/uploads/2009/02/Fast-Facts-Final-6-11.pdf
[3] Gao, C., et al. “Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets.” Signal Transduction and Targeted Therapy. https://www.nature.com/articles/s41392-023-01588-0
[4] Griciuc, A., et al. “Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta.” Neuron. https://pmc.ncbi.nlm.nih.gov/articles/PMC3706457/
[5] PR Newswire. “Aperture Therapeutics Announces Development Candidate Targeting CD33 to Restore Microglial Homeostasis in FTD and ALS.” https://www.prnewswire.com/news-releases/aperture-therapeutics-announces-development-candidate-targeting-cd33-to-restore-microglial-homeostasis-in-ftd-and-als-302620390.html
[6] Lauffer, M.C., et al. “Possibilities and limitations of antisense oligonucleotide-based therapies for monogenic disorders.” Nature Communications. https://www.nature.com/articles/s43856-023-00419-1
