Beyond amyloid and dopamine: emerging technologies reshaping neurology 

For a long time, neurological drug development has largely focused on the cells that ultimately die or malfunction. Alzheimer’s researchers chased amyloid and tau. Parkinson’s drug development centered on dopamine signaling. Rare disease programs often focused on replacing a missing protein or gene. 

However, the progress has been limited. Some genes are too large for conventional gene therapy vectors. Many therapies struggle to reach the brain in sufficient quantities. But our understanding of these conditions has also improved. Blood-brain barrier (BBB) dysfunction and neuroinflammation are now seen as drivers of disease and not secondary consequences. 

A number of emerging technologies are being developed around these bottlenecks. From next-generation gene delivery systems and therapies targeting the neurovascular unit to brain-penetrant treatments for lysosomal diseases and precision modulation of neural circuits, neurological drug development is changing. 

Breaking gene therapy’s size barrier 

Gene therapy has taken an important place in the treatment of neurological diseases over the past decade, but cargo size remains a limitation on what can and cannot be treated. 

The adeno-associated virus (AAV), the vector behind several approved gene therapies, can carry roughly 4.7 kb of genetic material. That is sufficient for many therapeutic genes, but not all of them. This forces researchers to either engineer around the problem or look for entirely different delivery systems. 

One example is the ATM gene, which is mutated in Ataxia-Telangiectasia (AT), a rare neurodegenerative disorder causing progressive loss of motor coordination, immunodeficiency, and increased cancer risk. The ATM coding sequence is around 9.2 kb, nearly twice the carrying capacity of AAV. The ABCA4 gene, associated with Stargardt disease, for example, also exceeds AAV’s limit, which is why companies such as AAVantgarde Bio are developing dual-vector approaches that split the gene across two separate AAVs. 

Rather than trying to squeeze ATM into a smaller package, researchers at the Institute of Science in Tokyo are taking a different approach. Their technology combines a helper-dependent, or “gutless,” adenoviral vector with the piggyBac transposon system, a DNA cut-and-paste mechanism that can permanently insert genetic material into the genome. Gutless adenoviral vectors can accommodate much larger genetic payloads, making them suitable for oversized genes such as ATM.  

The piggyBac component addresses another limitation of adenoviral vectors: while adenoviral DNA usually remains outside the genome, piggyBac can integrate the therapeutic sequence into host cells, enabling longer-term expression. 

According to the team’s preclinical data, the system achieved nearly complete transduction in AT-derived fibroblasts and maintained ATM expression over multiple cell passages. The researchers also reported restoration of DNA damage-response signaling and improved survival following exposure to DNA-damaging agents. The results are still at a very early stage.  

The Tokyo group’s approach isn’t an isolated effort to overcome gene therapy’s size constraints. Dual- and triple-AAV systems are being explored for large genes that cannot fit into a single vector. Lentiviral vectors offer greater cargo capacity and have already found clinical applications in some genetic neurological disorders through ex vivo approaches. The industry is also investigating non-viral platforms, including lipid nanoparticles, which could eventually offer greater flexibility than viral vectors. 

Treating the brain’s vascular system 

Neurological disease is usually viewed through the lens of neurons: which cells die, which proteins accumulate, which circuits fail. But the blood vessels that support and protect those neurons are getting more attention these days, too. 

This is often described as the neurovascular unit, a network that includes brain endothelial cells, pericytes, astrocytes, neurons, and immune-related interfaces. It keeps unwanted molecules out of the brain and also helps regulate blood flow, immune traffic, inflammation, and the environment surrounding neurons. Disruption of this system is now linked to Alzheimer’s disease, Parkinson’s disease, ALS, multiple sclerosis, and stroke. 

This gives another front to attack when it comes to neurological diseases. Some companies are now asking whether stabilizing the BBB itself could slow or reduce neurological damage. 

Lys Therapeutics is one example. Its lead candidate, LYS241, is a monoclonal antibody designed to block the pathological interaction between tissue plasminogen activator, or tPA, and NMDA receptors. According to the company, this interaction contributes to BBB dysfunction, neuroinflammation, and dopaminergic neuron degeneration in Parkinson’s disease. 

The clearest near-term case may be stroke, where vascular injury, reperfusion damage, inflammation, and BBB leakage are central. In Parkinson’s and other neurodegenerative diseases, the argument is more ambitious. If BBB breakdown and inflammation help sustain disease progression, then restoring vascular health could change the course of the disease. 

There’s another major trend in neuroscience around the BBB, which is to use it as a gateway. Roche’s Brainshuttle technology, for example, is built to carry therapeutic cargo across the BBB by engaging receptors on brain endothelial cells. Roche’s Alzheimer’s candidate trontinemab uses this approach to improve the delivery of an anti-amyloid antibody into the brain. 

Focused ultrasound is also being tested to temporarily open the BBB and allow more drugs to enter targeted brain regions. In a small study combining focused ultrasound with aducanumab, researchers reported greater amyloid reduction in ultrasound-targeted regions, although the trial involved only three patients and remains very early. 

The rise of lysosomal biology 

For a long time, lysosomal storage disorders sat largely on the sidelines of neuroscience. Diseases such as Gaucher, Tay-Sachs, and Fabry disease were viewed as rare inherited conditions caused by the accumulation of molecules that cells could no longer properly break down. Researchers focused on replacing missing enzymes or reducing the buildup of toxic substrates, while the broader neuroscience field looked for answers to neurodegeneration. 

That began to change when scientists discovered that mutations in the GBA1 gene, which causes Gaucher disease, also increase the risk of developing Parkinson’s disease. Today, GBA1 is considered one of the strongest genetic risk factors for Parkinson’s. 

The discovery led to a reassessment of the role lysosomes play in brain health. Dysfunction in these lysosomal pathways has now been implicated not only in Parkinson’s disease, but also in Alzheimer’s disease and several other neurodegenerative disorders. 

One challenge has been translating that link into treatments that reach the brain. Existing enzyme replacement therapies can soften some symptoms of lysosomal storage disorders but generally do not cross the BBB. 

Researchers at Boston Children’s Hospital are trying to address that limitation through a new generation of brain-penetrant glucosylceramide synthase (GCS) inhibitors. The compounds target the production of glycosphingolipids that accumulate in several lysosomal storage disorders, while also being designed to enter the central nervous system. According to the Boston team, the most potent candidate demonstrated brain penetration in preclinical studies and showed substantially greater activity than existing substrate reduction therapies. 

Companies such as Gain Therapeutics have developed programs aimed at restoring glucocerebrosidase function in Parkinson’s disease. It is a field that needs more clinical validation, though. Not every program has succeeded; Sanofi’s investigational GCS inhibitor Venglustat failed to deliver results in Parkinson’s disease. However, the story didn’t end there for Venglustat as Sanofi announced in March it had obtained Breakthrough Therapy designation in type 3 Gaucher disease from the FDA, after it reported positive phase 3 results. 

Fine-tuning brain circuits 

When Bristol Myers Squibb’s Cobenfy reached the market in 2024, much of the attention focused on schizophrenia. But the approval also meant renewed interest in muscarinic receptors. 

The biology itself is not new, as we have been aware for years of muscarinic receptors’ involvement in memory, cognition, and other brain functions. But as it is often the case, knowing a biological fact doesn’t automatically mean you’ll find clinical success in exploiting it. Directly activating these receptors can be difficult because several closely related receptor subtypes are found throughout the brain and body, making side effects hard to avoid. 

But today, researchers at Penn State are developing compounds known as positive allosteric modulators, or PAMs, that target the M1 muscarinic receptor. These compounds are designed to strengthen the response to acetylcholine, the brain’s natural signaling molecule. Instead of forcing a receptor into an active state, researchers are looking for ways to adjust signaling more subtly.  

From symptoms to bottlenecks 

Although these technologies target different diseases and mechanisms, they share the common objective of addressing the bottlenecks that have limited neurological drug development. 

These technologies remain at a very early stage, and whether they will ultimately succeed remains uncertain. However, they show how the next generation of neurological therapies may differ from the approaches that have dominated the field for decades. 

Many of these emerging technologies are tackling the underlying biological bottlenecks that have historically made neurological diseases so difficult to treat.