Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes

Neurodegenerative diseases (NDs) constitute a group of progressive disorders that primarily impact neurons in the brain and spinal cord. Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are among the most prevalent NDs, significantly affecting both the individuals diagnosed and their families. These diseases share common features such as progressive neuronal degeneration, which leads to the gradual decline of motor, cognitive, and autonomic functions, although they affect different regions of the nervous system. They are commonly linked to the accumulation of atypical proteins in the brain, such as amyloid plaques and tau tangles in AD, which cause significant brain atrophy through the degeneration of neurons and synapses [1]; alpha‐synuclein (α‐syn) aggregates in PD, which lead to the progressive degeneration of dopaminergic neurons in the substantia nigra, resulting in motor impairments [2]; misfolded proteins like TAR DNA‐binding protein 43 (TDP‐43) or Superoxide dismutase 1 (SOD1) in ALS, which result in the loss of motor neurons and progressive muscle weakness [3]; and the huntingtin (HTT) gene mutation in HD, which results in an abnormally expanded polyglutamine stretch in the HTT protein, leading to toxic intracellular inclusions that disrupt normal cellular functions [4]. As a common characteristic, NDs involve neuroinflammation, mitochondrial dysfunction, and oxidative stress [5], which disrupt the protein clearance systems that normally remove damaged or misfolded proteins, such as autophagy and the ubiquitin‐proteasome system [6], which contribute to neuronal damage. Additionally, they exhibit symptoms steadily deteriorating over time, significantly impairing quality of life and ultimately resulting in mortality. Despite the increasing prevalence of these diseases, effective therapeutic strategies remain limited, and current treatments mostly focus on alleviating symptoms rather than preventing or reversing disease progression. The primary challenge in addressing NDs lies in their complex, multifactorial nature, encompassing genetic, environmental, and cellular factors.

Present pharmacological treatments, such as cholinesterase inhibitors (e.g., donepezil, galantamine, and rivastigmine) and N‐methyl‐D‐aspartate (NMDA) receptor antagonists (e.g., memantine) for AD; dopaminergic medications for PD; riluzole for ALS, and tetrabenazine and deutetrabenazine for chorea in HD, as well as antipsychotics, provide only limited symptomatic relief and do not stop or slow disease progression [7, 8, 9]. Moreover, these medications frequently exhibit adverse side effects and limited effectiveness in later stages of the disease [10]. On the other hand, emerging monoclonal antibody therapies, such as FDA‐approved aducanumab targeting amyloid beta (Aβ), and semorinemab aiming to disrupt tau propagation and aggregation, offer an innovative approach to addressing the pathogenic pathways in AD and tauopathies though their clinical efficacy remains under debate [11, 12]. In the case of HD, strategies such as gene silencing to reduce mutant HTT protein levels are being explored as potential therapies to slow disease progression [13]. Meanwhile, in PD, dopamine replacement therapies, such as levodopa combined with carbidopa, remain the gold standard for symptomatic treatment, although complications like motor fluctuations and dyskinesias often arise with prolonged use [14]. Despite notable progress, obstacles in drug therapy for NDs persist. Many drugs fail to traverse the blood–brain barrier (BBB) effectively, reducing their therapeutic efficacy, and patient‐specific variations in disease pathology complicate treatment responses, requiring the development of personalized medicine approaches to optimize therapeutic outcomes.

A promising novel therapy is gene therapy, which offers several advantages primarily by addressing the genetic causes rather than just alleviating symptoms. It can provide long‐term or even permanent solutions by delivering functional genes to replace defective ones, or by silencing harmful genes. Moreover, gene therapy can potentially target the molecular mechanisms that lead to neurodegeneration, offering a more precise and disease‐modifying treatment than conventional therapies. However, gene therapy shows significant challenges as well, such as delivering therapeutic genes to the brain due to the BBB and ensuring their stable expression in neurons due to the brain's complex structure [15, 16]. Although gene therapy clinical trials for NDs have advanced progressively in recent years, they are in the early to mid‐development phases.

Stem cell therapies, which are the primary focus of this review, have emerged as a promising strategy for NDs. Unlike conventional pharmacological therapies that primarily alleviate symptoms with minimal disease‐modifying effects, stem cell therapies have the ability to repair damaged tissues, replace lost neurons, and modulate neuroinflammation. Despite their significant potential, they face several issues. One major concern is the risk of tumorigenesis, particularly with pluripotent stem cells. Additionally, there are limitations regarding the survival and integration of transplanted cells into host tissue, as well as the risk of uncontrolled differentiation or migration of these cells [17]. Alongside direct stem cell transplantation, an emerging field of research investigates the application of stem cell‐derived exosomes, nanovesicles that transport diverse biomolecules, including proteins, lipids, and RNA, capable of facilitating intercellular communication and impacting mechanisms underlying the disease [18]. Exosomes have multiple advantages over stem cell therapies, such as reduced risk of immunological rejection and tumorigenesis, since they do not include the direct transplantation of viable cells, difficulties associated with cell survival and engraftment may be avoided. Moreover, exosomes are capable of passing through the BBB with greater efficacy and possess the capacity to diminish neuroinflammation, facilitating neuroprotection resulting in cellular repair [19, 20]. Furthermore, exosomes are easier to apply and can be preserved for extended durations at low temperatures without losing their efficacy, rendering them more practical and economical for clinical applications in comparison to stem cells [21].

This review seeks to deliver a comprehensive evaluation of stem cell clinical trials conducted this far on NDs, in conjunction with preclinical and clinical investigations involving the nascent involvement of stem cell‐derived exosomes in AD, PD, ALS, and HD. By examining the latest preclinical studies and clinical trials, we aim to provide a comprehensive overview of how stem cell‐derived exosome therapies could revolutionize the treatments of NDs.

Stem cell therapies represent a promising advancement in the treatment of NDs due to their potential to repair impaired brain functions and slow disease progression. Various types of stem cells, including neural stem cells (NSCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs), have shown the ability to replace damaged or lost neurons, restore disrupted brain circuits, and integrate into injured brain regions, thereby ameliorating cognitive and motor impairments [22].

To analyze stem cell clinical trials conducted in NDs, we refined our list to 94 studies. This was achieved by searching ClinicalTrials.gov↗ with the terms "stem cells and Alzheimer's Disease," "stem cells and Parkinson's Disease," "stem cells and Amyotrophic Lateral Sclerosis," and "stem cells and Huntington's Disease" as separate queries, excluding studies that did not involve stem cell‐based cellular therapy in order to obtain a representative dataset. Each study was individually reviewed for inclusion. Trials with recruitment statuses of "suspended," "terminated," "withdrawn," or "no longer available" were excluded, while those labeled "completed," "not yet recruiting," "recruiting," "active, not recruiting,", "enrolling by invitation," and "unknown" were included. Studies other than those marked "completed" or "unknown" were grouped as "ongoing." Additionally, trials were categorized by their clinical phases, including those with unknown phases labeled as NA. The furthest phase each disease has come with stem cell therapy has also been below the graph (Figure 1).

The initial clinical trials employing stem cells for the treatment of the above‐mentioned NDs began in 2007, starting with ALS, followed by AD and PD in 2011, and much later with HD in 2014. These trials mainly focused on assessing the effectiveness of stem cells in NDs and aimed to evaluate the safety and feasibility of transplanting stem cells into patients through various delivery methods, including intravenous or intrathecal injection, and also direct transplantation into the brain. Out of the 94 clinical trials, if we ignore those with unknown study status, there are three Phase 3 trials in total (1 completed and 1 ongoing in ALS, and 1 ongoing in HD), ten Phase 2 trials (2 ongoing in AD, 2 completed and 1 ongoing in PD, 2 completed and 2 ongoing in ALS, 1 completed in HD), and one completed Phase 2/3 trial in ALS. The remaining are mostly Phase 1 and 1/2 trials, and a few early phase trials (Figure 1). In total, more than 8000 participants (patients and healthy controls) have enrolled in stem cell therapy trials across these four diseases. Notably, nearly 70% of these participants were enrolled in AD trials (Figure 2).

NSCs possess the distinctive ability to self‐renew and differentiate into both neurons and glial cells throughout the development of the central nervous system (CNS), making them particularly suitable for treating NDs [23]. NSC transplantation has demonstrated the potential to prevent neurodegeneration and promote regeneration through various mechanisms, including enhancing neuronal plasticity, reducing neuroinflammation, producing neurotrophic factors, and restoring dead cells [24]. However, their use comes with limitations. NSCs are primarily found in particular regions of the adult brain, making it impractical to obtain them from live donors for therapeutic purposes. Additionally, sourcing NSCs from fetal brains raises ethical concerns about the potential exploitation of human fetuses.

On the other hand, MSCs, often derived from bone marrow, adipose tissue, or umbilical cord tissue, are some of the most widely used stem cells in clinical trials (Figure 3A,B) due to their ability to modify the local microenvironment, support neurogenesis, promote cellular repair, and modulate immune responses, potentially improving cognitive and motor functions. Their immunomodulatory effects and secretion of trophic factors make them attractive for treating NDs, potentially alleviating neuroinflammation and enhancing tissue repair. MSCs are typically regarded as possessing a good safety profile, as they have a reduced propensity for tumor formation and can be used in autologous therapies to mitigate immunological rejection. However, challenges remain regarding the clinical application of MSC therapy. Issues such as cell survival, engraftment and the ability to direct MSC differentiation into neurons or other specific cell types are significant complications that must be overcome before broad clinical implementation [25]. While single MSC transplants are considered safe and do not trigger a significant immunological reaction, frequent administration of MSCs may lead to the development of allo‐antibodies, posing risks of immune complications [26]. Furthermore, MSCs display Major Histocompatibility Complex (MHC) class I, and they may stimulate allogeneic immune responses that cause tissue damage and inflammation recipients [27].

ESCs derived from early‐stage embryos possess the highest potential for differentiation into any cell type. However, their use is highly controversial due to ethical concerns. As a result, clinical trials involving ESCs in NDs are limited (n = 6), with one completed, one with unknown status, and three ongoing for PD, and one completed for ALS Figure 3A. In contrast, iPSCs, generated through the reprogramming of adult somatic cells, offer a less controversial alternative. iPSCs maintain comparable pluripotency while significantly reducing ethical concerns. Clinical trials using iPSCs have primarily focused on PD, with nine study records, one completed, one unknown, and seven ongoing. These trials predominantly involve the generation of dopaminergic progenitor cells for direct transplantation into the patients' brains [28]. Recently, there has been a shift toward iPSC and exosome‐based therapies, which provide better control over differentiation processes and minimize the risk of immunological rejection.

In addition to the source of stem cell isolation, the donor source of stem cells is also an important factor to be considered when designing the most suitable personalized treatment. The choice of donor source of stem cells can either be autologous or allogeneic. Even though allogeneic therapy is mostly preferred in AD and PD, autologous therapy has become prominent in ALS Figure 4. Autologous therapy is less complicated with no risk of rejection as the cells are isolated directly from the patient. However, elderly patients, as well as those with advanced disease stages, have the disadvantage of low quality and even quantity of stem cells. In contrast, allogeneic stem cells tend to be more abundant and healthier, but they now have a risk of immunogenicity resulting in graft vs. host disease [22]. Therefore, the source may be decided based on the disease, patient's condition, and availability of healthy stem cells.

The therapeutic potential of exosomes in NDs arises from their capacity to deliver neuroprotective and regenerative signals, cross the BBB, and minimize the risks associated with stem cell therapy [18]. According to preclinical studies, exosomes have been shown to deliver neuroprotective drugs, diminish neuroinflammation, and facilitate neuronal regeneration in animal models, underscoring their medicinal potential [47, 48, 49]. Moreover, engineered exosomes, modified to transport certain pharmaceuticals or genetic material, demonstrate potential in improving treatment effectiveness. These advancements place exosomes in the front of research focused on identifying more effective and targeted therapies for these severe conditions [46]. The subsequent sections will provide a detailed discussion of preclinical and clinical trials completed to date for AD, PD, ALS, and HD along with studies employing engineered exosomes.

This review emphasizes the progress in stem cell therapy for NDs, including AD, PD, ALS, and HD. Despite notable advancements, especially in early‐phase clinical trials, the scarcity of late‐stage trials highlights the necessity for additional investigations. The emergence of stem cell‐derived exosome‐based therapeutics provides a persuasive alternative to direct stem cell transplantation, facilitating less invasive methods for the delivery of therapeutic molecules across the BBB.

Exosomes, especially those originating from MSCs, have exhibited considerable preclinical efficacy in alleviating neuroinflammation, diminishing oxidative stress, and facilitating neuronal regeneration. Progress in exosome engineering, encompassing surface changes and augmented targeting abilities, has significantly expanded their therapeutic potential. Nonetheless, exosome‐based therapeutics are still in the preliminary phases of clinical investigation, with only three clinical trials presently underway (two for AD and one for ALS).

Our research group is also conducting research on the therapeutic effects of exosomes derived from stem cells, antioxidant‐loaded enriched exosomes, as well as transgenic exosomes expressing proteins potentially effective against neurodegeneration, in both in vitro and in vivo models of AD and PD.

Future initiatives should focus on broadening clinical trials to encompass more NDs, such as PD and HD, while also addressing the issues of scalability and standardization in exosome production. The rising interest in exosome‐based therapeutics, alongside technological progress and an enhanced comprehension of their therapeutic potential, is anticipated to propel revolutionary treatment techniques for NDs. These advancements may facilitate more accurate, efficient, and less invasive procedures, thereby enhancing patient outcomes in these NDs.

S.I., S.O., B.Y.K., S.R.M.S., and N.M.E.S. wrote the manuscript; S.I. designed the research; S.I., S.O., B.Y.K., S.R.M.S., and N.M.E.S. performed the research; S.I. and B.Y.K. analyzed the data.

No funding was received for this work.

The authors declare no conflicts of interest.