Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that still lacks an efficient therapy. The barriers between the central nervous system (CNS) and the blood represent a major limiting factor to the development of drugs for CNS diseases, including ALS. Alterations of the blood–brain barrier (BBB) or blood–spinal cord barrier (BSCB) have been reported in this disease but still require further investigations. Interestingly, these alterations might be involved in the complex etiology and pathogenesis of ALS. Moreover, they can have potential consequences on the diffusion of candidate drugs across the brain. The development of techniques to bypass these barriers is continuously evolving and might open the door for personalized medical approaches. Therefore, identifying robust and non-invasive markers of BBB and BSCB alterations can help distinguish different subgroups of patients, such as those in whom barrier disruption can negatively affect the delivery of drugs to their CNS targets. The restoration of CNS barriers using innovative therapies could consequently present the advantage of both alleviating the disease progression and optimizing the safety and efficiency of ALS-specific therapies.

Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients

“…However, numerous drugs targeting main pathological mechanisms involved in ALS have been tested in clinical trials, but failed to demonstrate a significant benefit, highlighting that the pathogenesis of ALS remains partially understood. Impairment of central nervous system (CNS) barriers may contribute to its mysterious pathogenesis and probably impacts the development and administration of therapeutic candidates [ 9 ].…”

“…They protect the CNS from neurotoxic compounds or drugs representing a major limit to the development of therapeutics targeting the brain. BBB/BSCB impairment has been known in ALS for a decade [ 11 , 12 , 13 ] and has been discussed in recent reviews highlighting its significance in the disease, via its putative implication in the pathogenesis mechanism, as a biomarker of disease outcome, and finally as required drug development strategy parameter [ 9 , 14 , 15 ]. Unfortunately, data published on BBB/BSCB disruption are too few to conclude on its role in the course of the disease.…”

Attenuation of amyotrophic lateral sclerosis via stem cell and extracellular vesicle therapy: An updated review

“…4 While much remains to be elucidated about the mechanism of motor neuron damage in ALS, one mechanism of pathogenesis relates to the influx of toxic blood-derived products, such as fibrin, thrombin, and hemoglobin, through damaged blood-central nervous system (CNS) barriers. [5][6][7] Both blood-brain barrier (BBB) and blood-spinal cord barrier permeability are well documented in the progression of ALS, raising the question as to whether therapeutics aimed at restoring barrier function may ameliorate damage and slow disease progression. 6,7 The blood-CNS barrier is composed of capillary endothelial cells and astrocyte end-feet, both of which may be rescued from damage by neuroprotective factors found in stem cell-derived extracellular vesicles (EVs).…”

Novel Therapeutic Opportunities for Neurodegenerative Diseases with Mesenchymal Stem Cells: The Focus on Modulating the Blood-Brain Barrier

“…Finally, recognizing that MSCs not only impact immune activation and neurodegeneration but also address disrupted vascular components has prompted the exploration of novel therapeutic targets and combination strategies. In addition to their impact on the BBB in the context of the CNS disorders covered in this review (PD, AD, MS, and stroke), the relevance of the BBB extends to other neurodegenerative conditions, including traumatic brain and spinal cord injury [ 250 , 251 , 252 ], amyotrophic lateral sclerosis [ 253 , 254 ], Huntington’s disease [ 255 ], and epilepsy [ 256 ]. However, the significance of the BBB as a target for MSC therapy in those disorders is still emerging.…”