Restoring brain barriers: an innovative approach for treating neurological disorders

Abstract

The complex etiology of neurological disorders is a major challenge to the identification of therapeutic candidates. Tackling brain vascular dysfunction is gaining attention from the scientific community, neurologists and pharmaceutical companies, as a novel disease-modifying strategy. Here, we provide evidence that at least 41% of neurological diseases and related conditions/injuries display a co-pathology of blood-brain and blood-spinal cord barrier alterations and dysfunctions, and we discuss why this figure may represent only a fraction of a larger phenomenon. We further provide clinical evidence that barrier status may contribute to pathological and functional outcomes in patients. Finally, we discuss drug candidates under development to repair brain barriers.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; BBB disruption; BSCB disruption; Claudin-5; Huntington’s disease; Multiple sclerosis; Parkinson’s disease; Therapeutic strategies; Tight junction.

Fig. 1

Timeline of milestone discoveries in BBB and BSCB structural alterations and dysfunctions in neurological disorders. This figure depicts research milestones encompassing the first use of the French term “barrière hémato-encéphalique” by Lina Stern in 1921 [303], later translated into “BBB”, the discovery of endothelial TJs in 1967 [304] and associated proteins (ZO-1 [305], occludin [306] and claudin-5 [307]) and the early use of DCE-MRI for diagnosis of MS lesions in patients [308] at the end of the 20th century. Rodent and human postmortem analyses of brain or spinal cord tissues to assess the extravasation of IgG, fibrin(ogen), albumin and/or hemoglobin provided the first demonstrations of BBB and BSCB leakage in neurological disorders, such as in AD [309, 310], ALS [119, 311], HD [16, 312], MS [313, 314] and PD [100, 101, 315]. In the last decade, advances in neuroimaging using DCE-MRI have paved the way for studying subtle BBB leakage in patients with neurological disorders, notably AD [96], HD [16] and PD [99], allowing earlier evidence/diagnosis of BBB dysfunction in the progression of neurological disorders than postmortem analyses

Fig. 2

Histogram and venn diagram analysis using publications reporting BBB and BSCB alterations and dysfunctions in neurological disorders. The histogram depicts the main characteristics of the 359 articles used for the survey of this review. About one third of these articles provided evidence in patients with neurological disorders, and the rest in animal models. The venn diagram highlights 54 neurological disorders for which BBB or BSCB alterations or dysfunctions were evidenced thus far in animal models and in humans. It shed light on 9 neurological disorders for which all the defects were reported: AD, ALS, cerebral cavernous malformation, epilepsy, HD, hemorrhagic stroke, major depressive disorder, MS and PD. Overall, this figure demonstrates the growing interest of the scientific and medical communities for barriers integrity, and the increasing number of pathologies for which BBB or BSCB alterations or dysfunctions are discovered over time

Fig. 3

BBB and BSCB alterations and dysfunctions in neurological disorders. Barriers between the blood and the parenchyma are essential to human health by maintaining brain and spinal cord homeostasis. When these barriers are readily interrupted (for example through a degradation of TJ proteins or increased vesicular activity), they leak circulating blood elements (such as fibrin(ogen) or IgG), and sometimes red blood cells in case of hemorrhagic transformation. The uncontrolled recruitment of immune cells into the parenchyma across the inflamed vascular wall (diapedesis) represents another major dysfunction of these barriers. Today, these BBB and BSCB alterations and dysfunctions, in particular, have been reported in ~ 41% of neurological diseases and injuries, suggesting that they may contribute to the pathogenesis of many neurological disorders. The heatmap highlights evidence found in animal models and in humans ranked from the most relevant to human patients’ health to the less relevant (from the exterior to the interior of the circle: dysfunctions in humans, alterations in humans, dysfunctions in animal models and alterations in animal models). Features of barrier alterations included in this heatmap are a loss of TJs and/or decreased protein levels of TJ-associated proteins (claudin-5, occludin and/or ZO-1). Features of barrier dysfunctions are a leakage of circulating elements into the parenchyma and/or an increased/uncontrolled immune cell trafficking across the BBB. The numbers in the squares indicate the number of articles depicting these alterations and dysfunctions, and corresponding articles are reported in Supplementary Table 1

Fig. 4

High-level mechanism of action landscape of therapeutic agents targeting BBB and BSCB alterations and dysfunctions as a treatment for neurological disorders. The left panel represents the barrier interface in physiological condition, whereas the right panel represents the barrier interface in neurological disorders with barrier alterations. Several dysfunctions of brain barriers occur in neurological disorders; herein, we define dysfunctions by the leakage of blood elements and red blood cells into the parenchyma, and increased/uncontrolled trafficking of immune cells across the BBB or BSCB. Strategies to reduce blood-to-brain leakage consist in: (1) restoring normal levels of TJ proteins by promoting their expression through the activation of specific receptors (β₁-integrin or WntR; indicated in green), or by inhibiting/blocking receptors or intra/extracellular molecules or enzymes known to degrade TJs (VEGFR, SEMA4D, LpPLA2, ROCK2, sVCAM1, Hcy and (s)RGMa; indicated in orange), or (2) by adding an exogenous synthetic biopolymer to “replace” TJs. Strategies to reduce blood-to-brain immune cell entry consist in: (3) blocking the adhesion of immune cells to endothelial cells by blocking their interaction through α₄β₁-integrin with VCAM1 present at the cell surface (indicated in orange), or (4) by blocking the interaction of circulating tPA with GluN1-NMDAR present at the surface of endothelial cells to reduce the extravasation of immune cells across the BBB (indicated in orange). An alternative or complementary strategy to BBB repair aims at blocking one blood element (fibrin) present in the parenchyma to reduce neuroinflammation and neurodegeneration. Tysabri^® (i.e., Natalizumab) was added to this figure as the standard of care for reducing immune cell migration across the BBB in patients with RRMS. ECM: extracellular matrix; GluN1-NMDAR: GluN1 subunit of NMDAR; Hcy: homocysteine; IgG: immunoglobulin G; ITG: integrin; Lp-PLA2: lipoprotein-associated phospholipase A2; NMDAR: N-methyl-D-aspartate receptor; (s)RGMa: (soluble) repulsive guidance molecule a; ROCK2: Rho-associated coiled-coil containing protein kinase 2; RRMS: relapsing-remitting multiple sclerosis; SEMA4D: semaphorin 4D; sVCAM1: soluble VCAM1; TJ: tight junction; tPA: tissue plasminogen activator; VCAM1: vascular cell adhesion molecule 1; VEGFR: vascular endothelial growth factor receptor; WntR: Wnt receptor; α₄β₁-ITG: α₄β₁subunit of ITG; β₁-ITG: β₁ subunit of ITG

Fig. 5

Drug development pipeline of therapeutic agents targeting BBB and BSCB dysfunctions for the treatment of neurological disorders. This figure depicts drug candidates in preclinical and clinical drug development for the treatment of BBB and BSCB dysfunctions (from companies’ pipeline online, and clinicaltrials.gov, accessed May 3^rd, 2025). The administration route, the development stage, and the therapeutic modality are indicated whenever known for each drug candidate (name underlined in bold). Systemic administration routes include i.v., i.a., and s.c. For any agent at early developmental stage, we have reported the pathology and administration mode envisioned by the company for clinical trials in patients. Clinical trials are indicated as ongoing or completed (year of completion indicated). Tysabri^® (i.e., Natalizumab) was added to this comprehensive SWOT analysis as the standard of care for reducing immune cell migration across the BBB in patients with RRMS. *clinical trial not disclosing brain barriers integrity biomarkers in the summary published on clinicaltrials.gov; CCM: cerebral cavernous malformation; CIS: clinically isolated syndrome; HAM: human T-cell leukemia virus type 1-associated myelopathy; i.a.: intraarterial; i.v.: intravenous; mAb: monoclonal antibody; MSA: multiple system atrophy; ND: neurological diseases; NVD: neurovascular diseases; RRMS: relapsing-remitting multiple sclerosis; s.c.: subcutaneous; SCI: spinal cord injury; SWOT: strengths, weaknesses, opportunities and threats

Fig. 6

Key features of therapeutic agents designed at repairing BBB and BSCB integrity. The upper panels depict two pie charts showing the respective proportions of each modality and development stage of all drug candidates currently being developed. On the lower panels, the two pie charts show the respective proportions of each administration route for agents at clinical stage in healthy volunteers or in patients, and of the number of patients with neurological disorders being /planned to be enrolled in clinical trials for evaluation of brain barriers therapeutic candidates. *clinical trial completed; **final number of patients enrolled; PoC: proof of concept