Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS), are characterized by acute or chronic progressive loss of one or several neuronal subtypes. However, despite their increasing prevalence, little progress has been made in successfully treating these diseases. Research has recently focused on neurotrophic factors (NTFs) as potential regenerative therapy for neurodegenerative diseases. Here, we discuss the current state of knowledge, challenges, and future perspectives of NTFs with a direct regenerative effect in chronic inflammatory and degenerative disorders. Various systems for delivery of NTFs, such as stem and immune cells, viral vectors, and biomaterials, have been applied to deliver exogenous NTFs to the central nervous system, with promising results. The challenges that currently need to be overcome include the amount of NTFs delivered, the invasiveness of the delivery route, the blood–brain barrier permeability, and the occurrence of side effects. Nevertheless, it is important to continue research and develop standards for clinical applications. In addition to the use of single NTFs, the complexity of chronic inflammatory and degenerative diseases may require combination therapies targeting multiple pathways or other possibilities using smaller molecules, such as NTF mimetics, for effective treatment.

Over the past two decades, significant advances have been made in the field of regenerative medicine. However, despite being of the utmost clinical urgency, there remains a paucity of therapeutic strategies for conditions with substantial neurodegeneration such as (progressive) multiple sclerosis (MS), spinal cord injury (SCI), Parkinson’s disease (PD) and Alzheimer’s disease (AD). Different cell types, such as mesenchymal stromal cells (MSC), neuronal stem cells (NSC), olfactory ensheathing cells (OEC), neurons and a variety of others, already demonstrated safety and regenerative or neuroprotective properties in the central nervous system during the preclinical phase. As a result of these promising findings, in recent years, these necessary types of cell therapies have been intensively tested in clinical trials to establish whether these results could be confirmed in patients. However, extensive research is still needed regarding elucidating the exact mechanism of action, possible immune rejection, functionality and survival of the administered cells, dose, frequency and administration route. To summarize the current state of knowledge, we conducted a systematic review with meta-analysis. A total of 27,043 records were reviewed by two independent assessors and 71 records were included in the final quantitative analysis. These results show that the overall frequency of serious adverse events was low: 0.03 (95% CI: 0.01–0.08). In addition, several trials in MS and SCI reported efficacy data, demonstrating some promising results on clinical outcomes. All randomized controlled studies were at a low risk of bias due to appropriate blinding of the treatment, including assessors and patients. In conclusion, cell-based therapies in neurodegenerative disease are safe and feasible while showing promising clinical improvements. Nevertheless, given their high heterogeneity, the results require a cautious approach. We advocate for the harmonization of study protocols of trials investigating cell-based therapies in neurodegenerative diseases, adverse event reporting and investigation of clinical outcomes.

Multiple sclerosis (MS) is a chronic neurological disorder involving immune‐mediated demyelination and neurodegeneration in the central nervous system (CNS). Current therapies primarily target inflammation, with limited strategies to promote remyelination or neural repair. This study explores the therapeutic potential of Brain‐Derived Neurotrophic Factor (BDNF) delivered via an adeno‐associated virus (AAV) vector to enhance remyelination and improve cognitive function in a subchronic cuprizone (CPZ)‐induced demyelination mouse model. Sixty female C57BL/6 mice were used, with half receiving a 7‐week CPZ diet to induce oligodendrocyte loss. After demyelination, mice were treated with AAV‐BDNF, AAV‐eGFP, or saline injections into the corpus callosum (CC), followed by a 5‐week recovery phase. Behavioral assessments revealed improved cognitive performance with BDNF treatment, demonstrated by increased latency in passive avoidance tests. Immunofluorescence analysis showed increased proliferation and maturation of oligodendrocyte progenitor cells, with higher PDGFRα and CC1 markers, alongside elevated MBP. Transmission electron microscopy (TEM) indicated thicker myelin sheaths and a higher percentage of myelinated axons in AAV‐BDNF‐treated mice. Mitochondrial analyses revealed that BDNF treatment preserved mitochondrial integrity, with reduced swelling and improved structural regularity. Inflammatory markers showed no differences in Iba1 but indicated a trend of reduced astrocytic activation with BDNF. These results demonstrate that AAV‐BDNF therapy enhances remyelination, myelin integrity, mitochondrial structure, and cognitive function in a CPZ model, underscoring its potential for treating MS. BDNF‐based strategies may offer innovative avenues to improve neurological recovery and address unmet needs in MS management.

This doctoral thesis examines the role of brain derived neurotrophic factor (BDNF) in multiple sclerosis (MS) across complementary levels of investigation, from mechanistic concepts to human data. A comprehensive review first summarizes current knowledge on neurotrophic factors, highlighting BDNF as a key regulator of neuronal survival, synaptic plasticity and oligodendrocyte maturation, and outlining its potential as a target for remyelination and neuroprotection in neuroinflammatory and neurodegenerative diseases. Building on this framework, an in vitro pilot study in neonatal mouse oligodendrocyte progenitor cell cultures and organotypic brain slices shows that recombinant BDNF promotes differentiation into mature oligodendrocytes and increases myelin formation in a time and concentration dependent manner. In an in vivo cuprizone model of demyelination, local AAV mediated BDNF overexpression in the corpus callosum enhances the density of mature oligodendrocytes, improves myelin ultrastructure and is accompanied by better performance in a hippocampus dependent memory task, supporting a pro remyelinating and functionally meaningful effect of regional BDNF supplementation. The clinical study investigates whether these experimental findings are mirrored at the systemic level by relating serum BDNF to cognition and anxiety in 64 MS patients and 29 healthy controls. Patients with relapsing remitting and progressive MS show marked impairments in verbal learning and processing speed, and elevated anxiety scores, with the most pronounced deficits in progressive MS. Serum BDNF levels are higher in progressive MS compared with controls, yet they do not display robust or consistent associations with cognitive performance or anxiety after adjustment for age and disability. This suggests that peripheral BDNF reflects a complex interplay of neurodegeneration, inflammation, treatment and compensatory mechanisms, rather than providing a simple linear translation of the experimental effects. Taken together, the work supports BDNF as a promising therapeutic candidate for enhancing remyelination and neuroprotection, while underscoring the limitations of serum BDNF as a standalone biomarker of cognitive or emotional outcomes in MS. Future research should focus on longitudinal designs, integration of multimodal biomarkers and clinically feasible strategies for targeted BDNF delivery to bridge the gap between preclinical efficacy and patient level application.