It is hard to determine if the field of central nervous system (CNS) disease treatment is entering a “new era” of definitive breakthroughs or incremental advancements. At times it seems like a Cambrian explosion of innovation, but at other times there are disappointing setbacks.

Easing the ability to cross the blood brain barrier opens a possible floodgate of previously unavailable brain treatments.”

On 31 January 2024, Biogen pulled its once-encouraging Alzheimer’s drug, Aduhelm, from the market. A combination of both corporate and regulatory missteps, as well as milquetoast efficacy, doomed Aduhelm to a year of bleak sales and controversy, but just a week before the market withdrawal a potential breakthrough was announced. Researchers at the School of Engineering and Applied Sciences, University of Pennsylvania, announced promising results modeling mRNA delivery across the blood brain barrier using lipid nanoparticles (Han et al., Nano Lett, 2024). Easing the ability to cross the blood brain barrier opens a possible floodgate of previously unavailable brain treatments.

Easing the ability to cross the blood brain barrier opens a possible floodgate of previous unavailable brain treatments.

AI is a rapidly advancing field of study

Despite the brain and the CNS system being, “The last organ system where many aspects of our understanding of the underlying biology of disease remain uncertain,” as previous FDA Commissioner Scott Gottlieb once said (PharmaVoice, September 2018), the pace of understanding, treatment options, and creative approaches to CNS research is nothing short of dizzying.

Benedict C. Albensi, PhD, BCMAS, CRQM, Professor and Chair of the Department of Pharmaceutical Sciences at Nova Southeastern University in Florida, whose lab focuses on mitochondrial dysfunction and sex differences in Alzheimer’s disease, sees interesting potential in several areas of CNS disease treatments.

“The application of AI [artificial intelligence] to diagnostics, particularly with respect to magnetic imaging, is a rapidly advancing field of study. It’s proven to be very effective for breast cancer and now we’re seeing benefits in CNS as well,” he says.

Few regions are as rife with CNS disease study and new treatments as the Nordics, and this also includes applying AI.”

Few regions are as rife with CNS disease study and new treatments as the Nordics, and this also includes applying AI. For example, the Danish Research Centre for Magnetic Resonance and the University of Oslo’s Center for Lifespan Changes in Brain and Cognition are applying AI to neuroimaging data for various purposes, such as identifying brain biomarkers for early detection of CNS diseases.

Non-pharmacological approaches, such as electrical and magnetic stimulation, have also shown value in CNS. Deep brain stimulation (DBS), which works by administering direct electrical pulses to different parts of the brain, is making strides in the treatment of CNS diseases such as epilepsy, Parkinson’s, and dystonia (a movement disorder), among many others. DBS is likely to progress more rapidly due to ongoing advancements and applications of AI, Dr. Albensi predicts.

In the Nordics, Sweden’s Karolinska University Hospital, a global leader in DBS, applies innovative combinations of MRI and electrophysiological data to increase target and circuit specificity, as well as reduction of DBS side effects.

Left: Benedict C. Albensi, Professor and Chair of the Department of Pharmaceutical Sciences at Nova Southeastern University

Brain-Computer Interface

A significant indicator of CNS disease treatment progress came on the same day as the Biogen Aduhelm announcement. Elon Musk’s Neuralink company announced that its brain-computer interface (BCI) device was implanted in its first human subject implant since FDA IND clearance in May 2023. BCI is poised to expand not only due to anticipated advancements in AI, but because it is expected to be used for another large market: gaming and entertainment. In CNS treatment, BCI has the potential to address spinal cord injuries by facilitating communication between brain signals and devices such as prosthetic limbs, wheelchairs and perhaps recover some degree of motor function itself.

In CNS treatment, BCI has the potential to address spinal cord injuries by facilitating communication between brain signals and devices such as prosthetic limbs, wheelchairs and perhaps recover some degree of motor function itself.”

In Sweden, BCI researchers at Lund University recently published an open-source BCI framework, released under MIT license, intended to expedite the next generation of BCIs (Nilsson et al., Front. Hum. Neurosci., 2023).

A far more complex understanding

Dr. Albensi notes how brain research and CNS disease treatments are following in the footsteps of oncology. “When I was young, if you were diagnosed with cancer it was essentially a death sentence. Thankfully, that’s not the case anymore. We now have a much better understanding of cancer, and that not all cancers are created or treated equally,” he says.

In the last several decades the field of oncology has moved from that singular diagnosis of ‘cancer’ to intensively granular understandings of how cancer manifests in different parts of the body at different life stages, due to genetics, environmental triggers, and other causes.

Alzheimer’s is currently used as a blanket term when in fact, like oncology, there is a multiplicity of manifestations and stages. What we study in my lab are metabolic associations with Alzheimer’s, such as mitochondrial dysfunction and transfusion, and potential similarities and overlap between Alzheimer’s and diabetes.”

Dr. Albensi notes that Alzheimer’s is currently used as a blanket term when in fact, like oncology, there is a multiplicity of manifestations and stages. “What we study in my lab are metabolic associations with Alzheimer’s, such as mitochondrial dysfunction and transfusion, and potential similarities and overlap between Alzheimer’s and diabetes,” he explains.

In addition to metabolic mechanisms, there are significant differences in characteristics and treatments for early versus late stage Alzheimer’s, as well as genetic or toxicity related Alzheimer’s, and the impact of genetic profiling and potential applications of gene therapy. Dr. Albensi anticipates a near future that will realize a far more complex understanding of Alzheimer’s not as a single disease, but as a category, with more effective treatments as a result.

Differentiation has proven effective in other CNS disease treatments, specifically dementia where there’s frontotemporal dementia, vascular dementia, Lewy body dementia, and targeting treatments accordingly has shown to be greatly beneficial.

New approaches

The quest for greater CNS certainty and understanding has yielded other interesting approaches, for example the study of “super-agers”, people aged 80 or older who test as well as, or even better, than young people in memory, cognition, and attention functions. These studies expand the understanding of core memory and other CNS functions.

Digital interventions are having an impact on CNS disease treatments as well. For example the Danish Brain+’s CST Assistant, a dementia treatment developed in conjunction with VIA University College, is a collection of cognitive stimulation therapies delivered digitally.

For example the Danish Brain+’s CST Assistant, a dementia treatment developed in conjunction with VIA University College, is a collection of cognitive stimulation therapies delivered digitally.”

Nordic Brain Tech addresses migraines via Brain Twin, a digital headache diary providing important data for diagnosis and follow up of headache conditions, and is also developing a remote biofeedback medical device for the treatment of migraines.

The field of CNS disease has always been characterized by stops and starts. While that’s likely not to change, and magic bullets are likely few and far between, the incremental advancements, pace of innovation, and creative approaches give rise to great optimism for the near-term and long-term future of CNS disease treatments.

About the Author

Sheila Mahoney-Jewels, MBA, is a Drug Development Cross-Functionalist and Science Writer. She is heavily involved in industry adoption of advanced safety analytics, data science and application of AI and ML to drug development operations.