Welcome to Part 4 of our series about the blood brain barrier (BBB)! Here, we highlight the rising global burden of neurological disorders, and recap on the challenges surrounding drug safety and toxicity in relation to the BBB. As industry speeds ahead with novel therapeutic approaches to neurological and non-neurological diseases, such as adeno-associated virus (AAV)-based gene therapies, CAR-T cell therapies, and gene-editing therapies, the need to understand safety and toxicity in relation to BBB penetration has never been more urgent.
According to a report published by the World Health Organization (WHO), up to one billion people worldwide were affected by a neurological disorder in 2006, and 6.8 million people were dying every year as a result of their condition. 50 million people were estimated to suffer from epilepsy while 24 million people were estimated to have Alzheimer disease (AD) or other forms of dementia.
Just 16 years later in 2022, the WHO published new figures estimating that 55 million people worldwide were living with some form of dementia, and almost 10 million new cases are diagnosed every year. The WHO expects this number to reach 78 million in 2030 and 139 million in 2050. These alarming figures on dementia are just a snapshot of the global burden of neurological conditions as a whole, which has been steadily increasing for the past three decades. Other significant neurological conditions include stroke, migraine, traumatic brain injuries, brain cancers, neurological infections, multiple sclerosis (MS), amyotrophic lateral sclerosis and Parkinson disease (PD).
Surge in brain diseases while therapeutic progress lags far behind
While the increased prevalence in neurological conditions is most pronounced in low- and middle-income countries, further surges are expected globally in response to population growth, aging and increased life expectancy, as well as changes in risk factors such as diet, obesity, smoking, alcohol consumption, and other lifestyle factors.
Sadly, despite decades of research aimed at understanding the underlying causes of neurological disorders, intense drug development efforts to create new therapies and a large number of clinical trials, the majority of these conditions remain poorly treated and incurable.
Today, AD, PD and MS represent three of the most prevalent neurodegenerative diseases. While the exact cause of disease remains unknown in all cases, it is well-established that damage to the BBB is implicated in disease progression. At present, the only treatments available for AD, PD and MS are drugs that either help to control symptoms but don’t touch the (unknown) root cause of disease, or more recently approved drugs that were designed to target some specific aspect of disease, but for which long-term clinical benefit remains to be demonstrated. In all cases, the available or upcoming treatments fall roughly into the following categories:
- Small molecules: Enzyme inhibitors, e.g., acetylcholinesterase (AChE) inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists to treat memory problems associated with AD, antipsychotics or antidepressants to treat behavioral and psychological symptoms that arise in AD and PD, synthetic forms of dopamine or dopamine agonists to boost dopamine levels in the brain in PD patients, drugs to control tremors and involuntary movements in PD, and muscle relaxants, steroids and medications to counteract fatigue and other physical symptoms in MS.
- Biologics: For example, monoclonal antibodies, such as aducanumab (FDA-approved in 2021) and lecanemab (FDA-approved in 2023), both of which reduce beta-amyloid plaques in AD. Natalizumab (FDA-approved in 2004, EMA-approved in 2006), which is designed to prevent T cells from attacking myelin tissue in MS. No disease-modifying therapy has been approved for PD.
- Single-dose AAV-based gene therapies: No gene therapies have yet been approved for AD, PD or MS, but a number of clinical trials are ongoing to evaluate the safety and efficacy of gene therapy candidates that can deliver a functional copy of a disease-associated gene directly to the brain on a CNS-tropic viral vector, thus overcoming the challenge of penetrating the BBB.
- CAR-T therapies: Results of a study carried out at Washington University School of Medicine in 2022 suggest CAR-T therapy as a novel strategy to treat MS by blocking the activity of pathogenic T cells at the myelin sheath, with encouraging signs of benefit in a mouse model of MS.
- Stem cell therapies: Currently, strategies based on human iPSC-derived dopaminergic neurons are the frontrunner in finding a curative stem-cell transplant treatment for Parkinson’s Disease.
As outlined in Part 2 of this series, better BBB models will advance drug development for neurological as well as non-neurological diseases by:
- Helping to unravel mechanisms of diseases in which damage to the BBB is implicated, e.g., stroke, MS, amyotrophic lateral sclerosis (ALS), PD, and other neurodegenerative disorders. This should lead to advances within new target identification, and thus open new avenues for treatment.
- Allowing drug developers to reliably test the permeability of all drug candidates across the BBB in a reproducible way that translates to the in vivo human-relevant setting. It is estimated that about 99% of all CNS-targeting drugs are plasma-bound and do NOT penetrate the human BBB.
- Making it possible to reliably monitor the therapeutic benefit and toxicity of novel CNS drug candidates prior to clinical trials.
Major advances in treatment of non-neurological diseases but BBB toxicity a concern
While progress in treating neurological diseases has been slow overall, great strides have been made in the treatment of several rare genetic diseases and blood cancers throughout the last decade, owing largely to the emergence of novel gene therapies and cell-based therapies.
Since the landmark FDA approval of the first CAR-T therapy, Kymriah (Novartis), in 2017, for the treatment of acute lymphoblastic leukemia in children and young adults, more than 20 cell and gene-based therapies have since been approved in the U.S. (FDA) and Europe (European Medicine Agency) to treat various blood cancers, bladder and prostate cancer, hemophilia, retinal dystrophy, ß-thalassemia, and other diseases (see here for a recent overview).
Although in their infancy, these new treatment modalities have transformed the lives of many people worldwide. CAR-T treatments have led to dramatic results for many cancer patients with total elimination of disease in some cases, while AAV-based gene replacement therapies such as Zolgensma (marketed by Novartis, for the treatment of spinal muscular atrophy), and Luxturna (marketed by Spark Therapeutics, for the treatment of RPE65-associated retinal dystrophy), can ameliorate symptoms and improve life quality in children for whom no other treatment was previously available.
No gene-editing therapies have yet been approved, but Vertex Pharmaceuticals and CRISPR Therapeutics jointly-developed CRISPR-Cas9 candidate for sickle cell disease and transfusion-dependent ß-thalassemia is edging closer to a potential FDA approval this year, with positive Phase 3 results from 2 global clinical trials.
While we should be excited about novel therapeutic modalities that might hold cures to the most prevalent and devastating diseases, a study carried out at University of Pennsylvania (UPenn) reminds us that what we know about the BBB so far is only scratching the surface. In an article published in Cell in 2020, researchers at Perelman School of Medicine, UPenn, report for the first time that CD19, which is the most widely-used target across CAR-T cell therapies, is expressed in human brain mural cells, such as pericytes. These cells surround the endothelium and are critical for BBB integrity, and the findings point towards CD19 expression as an explanation for the severe neurotoxicity seen in a subset of individuals receiving CAR-T therapies. Importantly, comparable levels of CD19 expression were not recapitulated in mouse mural cells, highlighting a serious limitation of mouse models in CAR-T safety and toxicity assessments.
Gaps in understanding can lead to risky assumptions
In summary, our incomplete understanding of what causes most human neurological diseases, the lack of robust and translatable human-relevant disease models, and the challenges associated with assessing BBB permeability have all contributed to the extremely high failure rates for CNS drugs in clinical trials, as well as unforeseen neurotoxicity in novel treatment modalities that are expected to revolutionize healthcare, e.g., the CD-19-targeting CAR-T therapies.
With modern research tools that allow us to unravel disease mechanisms and develop new drug targets, as well as new human-relevant BBB models, such as those based on induced pluripotent stem cells (iPSC) and three-dimensional spheroids and organoids that allow more in-depth BBB penetration studies, we hope that the disconnect between how we understand BBB biology and what is actually going on at the human BBB will lessen, to pave the way for new urgently needed therapies.
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Karen O’Hanlon Cohrt is an independent Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD, Karen relocated to Denmark where she held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Karen has been a full-time science writer since 2017, and has since then held numerous contract roles in science communication and editing spanning diverse topics including diagnostics, molecular biology, and gene therapy. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for learning helps her to keep abreast of exciting research developments as they unfold. Karen is currently based in Ireland, and you can follow her on Linkedin here.