Developing Translational Biologics for Brain Disorders

To put it simply, neurological diseases are challenging. The mechanisms of brain diseases are highly complex and intertwined with mechanisms of aging, genetics and environmental factors.

Alzheimer’s presents one of the starkest examples of this. Its complexity has thus far prevented researchers from developing an effective therapy that can slow or stop the progression of symptoms or prevent the disease from occurring. It is a neurological disorder filled with unknowns. We do not know, for example, what the relationship is between the hallmarks of Alzheimer’s, including brain atrophy and over-expression of amyloid plaques, and the cognitive decline that occurs in people with this devastating condition.

What we do know is the toll Alzheimer’s is taking on families. In the United States alone, 5.7 million people are living with the disease, and their caregivers (including family) provide 18.4 billion hours of care, valued at over $232 billion. The hunt for solutions to this growing public health problem is incredibly important.

Applying Biological Therapies in CNS
The majority of therapeutic approaches to central nervous system (CNS) diseases, including Alzheimer’s, have relied on small molecules aimed at specific targets, such as pathways, enzymes or receptors. These drug candidates have been identified as potential ways of modulating biological processes in a diseased brain by irreversibly changing neurochemical signals and altering the expression, aggregation or clearance of disease-related proteins. In this manner, small molecules have been successfully applied to alleviate symptoms in a variety of neurological diseases. For example, in Parkinson’s disease, the L-DOPA treatment is standard of care for patients and helps them to manage common motor symptoms, including tremors and dyskinesia. However, while L-DOPA treats these symptoms, it does not change the course of the disease.

The majority of treatments targeted for neurological diseases are small molecules of this nature—aimed at managing specific symptoms. Meanwhile, truly disease-modifying therapies have not been successfully developed for human use. There is, however, a new dawn for neuroscience drug development using biological therapies. These large-molecule drugs (antibodies, gene and cellular therapies, and enzyme replacement therapies) have shown success in other therapeutic areas, including rheumatoid arthritis and various forms of cancer. In CNS, the big obstacle currently is how to get these large molecules to the brain.

Getting Through the Blood Brain Barrier
The anatomy and structure of the central nervous system presents a unique challenge in treating diseases of the brain effectively. The blood-brain barrier limits how molecules cross to the brain. There is good reason for this. The blood-brain barrier protects the brain from harmful molecules and microbes that can compromise brain function. It also, unfortunately, prevents large molecule biologics and other large molecules from getting into the brain.

Researchers are trying to get around this barrier in innovative ways. One way is to use harmless viruses to deliver genes to brain cells and then use those cells to take up the extrachromosomal DNA and produce the desired large molecules. The evolution of biologics therapies in neuroscience has sparked research to address the challenges of utilizing large molecules to enter and to deliver a desired “payload” to brain tissue. Luckily, there are biological mechanisms, both active and passive, that can enhance the transportation of larger molecules through the blood-brain barrier. There are also non-invasive brain manipulations that can be introduced to facilitate the entry of molecules to the CNS in a controlled fashion.

One of these latest non-invasive techniques is focused ultrasound, which can be used to open the blood-brain barrier transiently, and is considered a safe method to enhance the transfer of desired molecules from the blood stream to the brain tissue. Future research and development will tell if these technologies will be important tools to deliver biologic therapies that would otherwise be obstructed by the blood-brain barrier.

Utilizing Human Stem Cells
Currently, the majority of the treatments developed for neurological conditions have not been efficacious or safe in clinical trials. One of the proposed obstacles to the successful development of a translational biological therapy is the use of non-human species as model organisms. From a human disease perspective, some of the currently utilized research models are more relevant than others, but they are still models.
 
As an alternative strategy, we are seeing a dramatic increase in use of inducible pluripotent stem cells (iPSCs), which have properties closer to patients than any non-human cells. iPSCs can be matured and differentiated to essentially any cell type, which adds an element of significant human relevance to the research. Increasing numbers of CNS disease-related drug development programs use iPSCs to explore mechanisms and effects of new therapies, hopefully leading to the successful development of effective therapies.

Cellular therapies are also an emerging tool in neuroscience research. The notion that undifferentiated cells of human origin could potentially replace damaged or unhealthy cells of a diseased brain is under intense research. Initial, albeit exploratory clinical research, suggests that in certain diseases and conditions, cellular therapies may be a therapeutic option in the future.

The Future of CNS Therapies
Future therapies for neurological diseases will have to employ a diverse range of approaches, utilizing large molecules, cell therapies or gene therapies. There has been a substantial increase in the number of biologics in drug development in recent years, and its prevalence continues to grow. According to Citeline, 24 percent of the neurological candidates in the preclinical pipeline are biologics. Despite the challenges present in accessing the brain, more biological therapies will be explored and developed for neurological diseases in the future, as they provide a number of options to explore for highly complex, but also chronic and slowly progressing, brain diseases.