Stem Cell Therapy for Alzheimer's Disease

Status and Challenges of Alzheimer's Disease Treatment

Current treatment focuses on inhibiting progression.

Alzheimer's disease is a progressive brain disease that causes memory impairment and a decline in cognitive function. It is the most prevalent type of dementia, and its significance continues to grow with population aging.

Current standard treatment employs cholinesterase inhibitors and NMDA receptor antagonists to balance neurotransmitters and slow the progression of symptoms.

However, these medications cannot halt disease progression or regenerate lost nerve cells.

The latest antibody drugs are also emerging, but limitations still exist.

Recently, antibodies targeting amyloid-beta and tau proteins—which are considered causative agents of Alzheimer's disease—have been developed, raising hopes. For instance, in clinical trials of the anti-amyloid-beta antibody lecanemab, it was reported to reduce cognitive decline by approximately 27% over an 18-month period.

However, this latest treatment only slows the progression of the disease and has not yet achieved a complete cure. Furthermore, there are risks of side effects such as cerebral hemorrhage and cerebral edema (ARIA), which necessitate cautious use.

Complex Pathology Complicates Treatment

Within the brain, Alzheimer's disease occurs.

• Amyloid-beta accumulation
• Abnormal accumulation of tau protein
• Chronic inflammation in the brain
• Oxidative stress
• Loss of synapses (connections between nerve cells)

These various pathological conditions occur concurrently.

Because of this complex disease mechanism,Conventional drugs that work on a single target do not provide sufficient effectiveness.As a result, there is no established method to stop the decline in cognitive function. This is a major challenge for patients and their families.

Against this backdrop, a novel therapeutic approach capable of broadly targeting multiple facets of pathology is critically needed.

New Possibilities in Alzheimer's Treatment Unlocked by Regenerative Therapy

Stem Cell Therapy Leading to 'Neural Regeneration'

Alzheimer's disease progresses via neuronal loss. Efforts to repair this degenerated neural tissue form a cornerstone of regenerative therapy, particularly Stem Cell Therapy.

Stem cells are specialized cells possessing the capacity for self-replication and differentiation into various cell types. Stem cells extracted from patients or donors are transplanted into the body to repair injured tissues and restore function.

The advantage of Stem Cell Therapy isCapable of working multidimensionally on complex pathologies that cannot be addressed by a single drug.. Similar to a "damaged city infrastructure repair team," this therapy provides multi-faceted support: calming nerve inflammation, protecting cells, and regenerating tissue.

Mesenchymal Stem Cells (MSCs) are a cell type of particular interest. Extractable from bone marrow, adipose tissue, and umbilical cord, they offer a favorable balance between safety and therapeutic efficacy, thus driving continuous global research expansion.

Why do umbilical cord-derived WJ-MSCs garner significant interest?

Mesenchymal stem cells (WJ-MSCs) derived from Wharton's jelly, the gelatinous tissue found within the umbilical cord, have garnered significant attention as a "next-generation cell source" in regenerative therapies.

The rationale is divided into four main aspects.

• Highly viable young cells, derived from neonates, exhibit minimal age-related degradation and possess exceptionally high proliferative capacity.
• Poorly detected by the immune system (low immunogenicity), with negligible MHC class II expression, resulting in infrequent post-transplant rejection reactions.
• Combining pluripotency and immune regulatory activity, capable of differentiating into various cell types including bone, cartilage, fat, and nerve-like cells, while also possessing anti-inflammatory functions.
• There are no ethical issues, as the umbilical cords are naturally obtained during childbirth, presenting minimal ethical concerns.

Particularly for neurodegenerative diseases such as Alzheimer's, which compromise the central nervous system, the approach of "young cells providing multidimensional support" is paramount. In this regard, WJ-MSCs can be conceptualized as "competent and dedicated young workers tasked with rebuilding the damaged brain city."

Given these characteristics, WJ-MSC is expected to be a cell with innovative potential in the treatment of Alzheimer's disease and other neurodegenerative diseases.

How Does Stem Cell Therapy Work in Alzheimer's Disease?

Stem cell therapy is not merely cell replacement.

Mesenchymal Stem Cells (MSCs) demonstrate particular advantages in addressing the complex pathology of Alzheimer's disease, fulfilling multifaceted roles such as modulating inflammation, providing neurotrophic support, clearing harmful substances, and repairing neural circuits—all operating concurrently.

Let us now explain each mechanism in a clear and understandable manner.

Reducing inflammation in the brain

In Alzheimer's disease, immune cells (microglia) become dysregulated and cause chronic inflammation in the brain. Inflammatory cytokines (e.g., IL-1β, TNF-α) are excessively released, damaging neurons.

MSCs curb this 'uncontrolled inflammation.' For instance, in animal experiments involving the intravenous administration of umbilical cord-derived MSCs, levels of the anti-inflammatory cytokine IL-10 increased, whereas inflammatory cytokines significantly decreased.

This helps alleviate chronic inflammation in the brain and creates an environment where nerve cells are protected.

Delivering Nutrients to Nerve Cells

MSCs also provide neurotrophic support. At the transplantation site, MSCs secrete a variety of trophic factors, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), and insulin-like growth factor (IGF-1).

These factors support injured neurons and promote new synapse formation (neural networks). Furthermore, exosomes (small vesicles) released by MSCs also contain microRNAs and proteins with neuroprotective functions.

As nourishing rain descends upon parched earth, neurons in the brain are empowered to regenerate.

Brain Waste Clearance

Deposition of amyloid-beta plaques and abnormal accumulation of tau protein are hallmarks of Alzheimer's disease. These toxic aggregates disrupt neuronal function.

MSCs not only suppress inflammation but also facilitate the degradation and removal of amyloid-beta accumulated in the brain. In experiments, it was reported that amyloid-beta accumulation was significantly reduced following MSC transplantation.

Analogous to a cellular detoxification system for the brain, MSCs remove abnormal proteins and foster an environment where neural cells can regain their optimal function.

Reconnecting the Damaged Memory Circuit

Neurons in the brain are interconnected via synapses to support memory and cognitive function, but in Alzheimer's disease, these circuits are damaged. MSC not only directly differentiate into neurons but also stimulate neural stem cells in the brain to promote neurogenesis and repair existing circuits.

In animal studies, enhanced neurogenesis in the hippocampus (a brain region involved in memory regulation) and increased synaptic density were observed. Additionally, MSCs contribute to the reduction of oxidative stress and the overall amelioration of the brain environment.

In other words, MSC functions as "an electrical technician repairing faulty memory circuits."

Evidence-Based Support: Effectiveness Revealed Through Research

Regarding the possibility of Stem Cell Therapy, animal trials and human clinical research continue to be conducted worldwide, and evidence supporting its effectiveness continues to accumulate.
Here, we present representative research results in an easy-to-understand way.

Recognized Ameliorative Effects in Animal Models

Research utilizing animal models of Alzheimer's disease (genetically modified mice and other small animal models) consistently indicates that mesenchymal stem cell (MSC) treatment results in the restoration of cognitive function and improvement in brain pathology.

For example, in mice receiving intravenous administration of human umbilical cord-derived MSCs, spatial learning and memory functions significantly improved 4 weeks post-administration, and amyloid-beta accumulation in the brain was also reduced. Furthermore, inflammatory cytokines decreased and anti-inflammatory cytokines (IL-10) increased, indicating that chronic brain inflammation was resolved.

Furthermore, techniques have been developed to efficiently guide MSCs to the hippocampus (the memory region) of mice. This is achieved by incorporating magnetic nanoparticles into the MSCs and then directing them using an external magnetic field. In these mice, both memory test performance and cognitive function showed improvement, alongside enhancements in neural functions critical for learning.

In this animal experiment:

• Decrease in inflammatory markers in the brain
• Reduction of oxidative stress
• Increased synaptic density
• Reduction of amyloid-beta and tau proteins

Protection and restoration of brain function have been recognized from various quarters.
Just like a "regeneration team that simultaneously repairs a city," MSC reconstructs the brain environment from various perspectives.

Preliminary Clinical Trial Results in Patients

Building upon the success of fundamental research, clinical trials involving patients with Alzheimer's disease have also commenced. While these early-stage trials primarily aim to confirm safety, promising results are already beginning to emerge.

For example, in an autologous stromal vascular fraction (SVF) transplantation trial into the brain ventricles, 8 out of 10 patients demonstrated stabilization or improvement in cognitive function, and in 3 patients, phosphorylated tau and amyloid-beta levels in cerebrospinal fluid were reduced.

Some cases have also demonstrated significant recovery of hippocampal volume.

Furthermore, in a clinical trial involving the intravenous administration of umbilical cord-derived MSCs conducted in Korea, safety was demonstrated and a tendency for the maintenance of Activities of Daily Living (ADL) was confirmed. (This trial is progressing to Phase IIa)

Of particular interest is the placebo-controlled, randomized, double-blind trial involving MSCs derived from Wharton's jelly (product name: Lomecel-B™), which was conducted in the United States.

In this trial, the group of patients who received MSCs demonstrated:

• A significant reduction in overall brain volume of approximately 48%.
• Approximately 62% reduction in hippocampal volume.
• Confirm reduction of inflammation with diffusion-weighted MRI.
• Upward trend in cognitive function scores and quality of life indicators

These findings demonstrate the potential of MSC to halt cerebral atrophy and slow the progression of symptoms.

Analogous to the task of reinforcing a compromised bridge to prevent its total collapse, stem cells play a role in attenuating the decline of brain function.

The Safety of Stem Cell Therapy: An Assessment of Potential Adverse Effects

Regarding Stem Cell Therapy, the primary concern is safety. Particularly when utilizing allogeneic MSCs (cells from other individuals), concerns about immune rejection and the risk of adverse effects are inevitable.

However, extensive research conducted to date demonstrates that treatment with MSCs, including WJ-MSCs, generally exhibits a high safety profile.

Confirmation of Safety in Early-Phase Clinical Trials

In an intravenous administration trial of umbilical cord-derived mesenchymal stem cells (MSCs) in Alzheimer's disease patients conducted in Korea, the post-administration symptoms observed were:

• Temporary fever (9 out of 9 cases)
• Mild headaches (7 cases)
• Nausea (5 cases)

All these symptoms resolved naturally within 36 hours. There were no side effects that resulted in long-term consequences.

In some patients, fever or nausea necessitated a one-day extension of hospitalization for precautionary observation. However, all cases improved with appropriate management, and no serious toxicity (dose-limiting toxicity) was identified.

Furthermore, long-term monitoring for up to 36 months did not reveal any novel serious adverse events. In conclusion, the intravenous administration of umbilical cord-derived Mesenchymal Stem Cells (MSCs) is feasible and safe.

The Risk of Adverse Events in the Overall Context of Stem Cell Therapy

Regarding Stem Cell Therapy in general, a 2022 meta-analysis evaluating the safety and effectiveness across various neurodegenerative diseases showed:

• The incidence rate of medication-related adverse events is approximately 3%.

It is very low.

Overall, cell-based therapy is a safe and viable therapeutic modality for neurological disorders.

WJ-MSC Special Security Force

Notably, WJ-MSC has additional security assurance.

• It is immunologically stealthy, allowing transplantation without immunosuppressants.
• Rejection reactions are extremely rare.
• The risk of tumor transformation is very low.

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) carry a risk of tumor formation due to their undifferentiated state. However, mesenchymal stem cells (MSCs) are "adult stem cells" that have achieved a certain degree of differentiation. To date, in clinical applications, there have been no reports of tumor formation following MSC transplantation.

On the contrary, MSC has:

• Anti-cancer activities
• Antifibrotic activity (tissue hardening)

It is reported, thereby including safer therapeutic cells for use.

Hope for the Future: New Strides Ushered In by Regenerative Therapy

Stem cell therapy for Alzheimer's disease has garnered significant attention as an innovative and unprecedented medical approach. In preclinical and early-phase clinical trials, promising results continue to be reported regarding improvements in memory function and the suppression of brain lesions. "Brain regeneration," once considered impossible, is now becoming a reality.

Stem Cell Therapy acts multidimensionally on the complex pathology of Alzheimer's disease, opening possibilities to access domains previously unattainable by prior treatments. Notably, Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) combine youthful vitality with a high safety profile, positioning them as a primary therapeutic agent in regenerative medicine.

Promising results are beginning to emerge in early clinical trials, demonstrating safety and symptom stabilization, and offering many patients and families tangible and robust hope. With advancements in treatment, the day when Stem Cell Therapy can contribute to enhancing the quality of life (QOL) for Alzheimer's patients and reducing the burden of care is drawing nearer.

The door is wide open for Stem Cell Therapy for Alzheimer's disease.

• A double-blind trial in patients with mild Alzheimer's using umbilical cord-derived MSCs (Lomecel-B). Clinical research demonstrating suppression of brain atrophy progression and mitigation of cognitive decline.
  Allogeneic mesenchymal stem cell therapy with laromestrocel in mild Alzheimer's disease: a randomized controlled phase 2a trial | Nature Medicine
• MSC transplantation derived from human umbilical cord in Alzheimer's model mice demonstrated improved spatial memory and a reduction in amyloid-beta in basic research.
  Human umbilical cord mesenchymal stem cells ameliorate cognitive impairments and reduce amyloid-beta deposition in a mouse model of Alzheimer's disease.
• A meta-analysis evaluating the safety and effectiveness of Stem Cell Therapy in various neurodegenerative diseases. The incidence rate of serious adverse events is approximately 3%.
  Are Cell-Based Therapies Safe and Effective in the Treatment of Neurodegenerative Diseases? A Systematic Review with Meta-Analysis
• Phase I safety trial of intravenous administration of human umbilical cord blood-derived MSCs in Alzheimer's patients conducted in Korea
  Safety and tolerability of allogeneic human umbilical cord blood-derived mesenchymal stem cells in patients with Alzheimer's disease
• A review summarizing the multidimensional effects of MSC therapy and its challenges in Alzheimer's models
  Mesenchymal stem cell therapy for Alzheimer's disease: Mechanisms and challenges
• Reports indicate that fat-derived cells (SVF) transplantation leads to stabilization and improvement of cognitive function, as well as a reduction in pathological proteins in cerebrospinal fluid.
  Safety and efficacy of autologous adipose-derived stem cells for Alzheimer's disease: a review of early clinical evidence
• Research on WJ-MSC manufacturing methods and characteristics. Confirms low immunogenicity, high proliferation capacity, and genetic stability
  Characterization and large-scale expansion of Wharton's jelly-derived mesenchymal stem cells for clinical applications