DDW Editor Reece Armstrong speaks to Brian Head, Professor of Anesthesiology at UC San Diego School of Medicine and Veterans Affairs Research Career Scientist, about challenges in Alzheimer’s drug discovery and how gene therapy research could provide promise for this challenging treatment area.  

RA: Why are early-stage, preventative treatments so important for Alzheimer’s disease? 

BH: AD is a devastating neurodegenerative disorder associated with progressive cognitive decline. Moreover, it estimated that over 400 million worldwide have pre-clinical AD, prodromal AD (mild cognitive decline), and/or AD dementia. While amyloid pathology is an important aspect of AD, AD pathophysiology is attributed to neuronal cellular alterations that include synaptic loss, mitochondrial abnormalities, and loss of trophic support. Interventions that can preserve synaptic function, normal mitochondrial respiration and dynamics, and provide trophic support could significantly improve neuronal cell health, even in the presence of amyloid burden. 

RA: What have been some of the major challenges in bringing effective treatments to market? 

BH: Billions of dollars have been spent on targeting amyloid-beta processing or clearance, with little clinical success. Although some, like Lecanemab and Donanemab, have shown success in clearing amyloid plaques, they have moderate effects on disease progression and are associated with ARIA (amyloid-related imaging abnormalities), suggesting that targeting amyloid alone is not sufficient to mitigate the progressive nature of AD and AD-related dementias (ADRD). As already mentioned, AD progression is associated with synaptic dysfunction and mitochondrial abnormalities, therefore genetic interventions that target neuroprotective and pro-survival signalling that converge upon synaptic and mitochondrial function may offer a promising approach to mitigate AD progression. 

RA: What are the limitations of current approaches to treating Alzheimer’s (tau proteins)? 

BH: Monogenic targeting focuses on reducing a known mutant genetic attribute believed to be associated with a disease. However, AD and ADRD are attributed to multiple factors, some of which are familial in nature (i.e., genetic), while others are sporadic and attributed to previous trauma (e.g., chronic traumatic encephalopathy (CTE) associated tauopathy) or environmental factors. Therefore, solely targeting one genetic component may not be the most effective way to combat the multifaceted changes that occur with AD and ADRD. 

RA: Following that how does your research differ from traditional approaches? 

BH: Our research focuses on over-expressing the membrane scaffolding protein, caveolin-1 (Cav-1), which organises and augments neuroprotective and pro-survival signalling pathways and improves mitochondrial health, function, and dynamics. While, neuron-targeted Cav-1 has no effect on reducing amyloid-beta or plaque formation in AD models, it still improves cognitive function, synaptic ultrastructure, and mitochondrial function. 

RA: Could you discuss the mechanism of action behind this gene therapy?  

BH: Cav-1 is a scaffold protein that organises membrane receptors in close proximity to augment high fidelity signal transduction (i.e., transducing an extracellular cue to the underlying intracellular environment). Our gene therapy, SynCav1, overexpresses Cav-1 specifically in neuronal cells. The expression is driven by a neuron-specific promoter, synapsin, so that the construct is not expressed in non-neuronal cells. Cav-1 over-expression in neurons augments synaptic receptor and trophic receptor signalling, synaptic vesicle trafficking, and restores mitochondrial function and dynamics (fission/fusion events) in AD. Because Cav-1 is involved in endocytic vesicular trafficking across multiple cell types, although not tested yet, one hypothesis is that Cav-1 facilitates communication from the extracellular environment to mitochondrial via vesicular transport. We are currently testing this in our lab. 

RA: Are human relevant disease models needed for Alzheimer’s to improve drug discovery research into this area?  

BH: Quite a bit of research now uses human neurons or human organoids derived from induced pluripotent stem cells (iPSCs). These model systems can be generated from human individuals with a known history of early onset familial AD (EOFAD), which would allow more precision medicine focused drug screening. However, similar to rodent models, it is difficult to recapitulate sporadic forms of AD using these models. With that in mind, if a drug screen proves efficacious in restoring function in multiple human neuronal or organoid models regardless of the type of familial mutation, it has the potential applicability for sporadic forms as well. 

RA: Why is the preserved hippocampal-dependent memory a critical aspect to consider in Alzheimer’s patients?   

BH: The hippocampus is an important component of the limbic system, critical for learning and memory, and undergoes significant degeneration and atrophy in AD patients. Furthermore, the hippocampus is necessary for communicating with other brain regions, therefore protecting the hippocampus may also assist in maintaining neuronal circuitry across multiple brain regions. 

RA: How essential would diagnostics be with a therapeutic approach such as this one?  

BH: It depends on what type of diagnostic one is seeking. Ideally, identifying some pre-AD indicator prior to synaptic and neuronal loss in living individuals would expose a temporal opportunity for when to deliver a potential therapeutic like SynCav1 well before significant brain atrophy has occurred. 

RA: Are there further plans to work with Eikonoklastes Therapeutics to bring this therapy into clinical trials?  

BH: Yes, Eikonoklastes Therapeutics is interested in multiple neurodegenerative indications that include AD, ADRDs and frontotemporal dementia (FTD). Eikonoklastes previously received orphan drug designation (ODD) from the FDA for SynCav1 as a treatment for ALS. They are currently under contract with a CDMO for CMC and GMP SynCav1 production, and plan to submit the Investigation New Drug application to the U.S. FDA in Q3 of this year. Eikonoklastesmhas moved ahead with GMP development and manufacturing. The FDA continues to recognize the importance of developing new treatments for rare diseases like ALS and for very large indications like Alzheimer’s that affect many citizens.  Eikonoklastes is currently trying to streamline gene and cell therapies with the FDA, which will hopefully benefit moving SynCav1 forward to treat neurodegenerative disease indications like ALS, AD, and ADRD. 

From DDW Volume 26 – Issue 4, Fall 2025 – Read the digital issue

Biography 

Brian Head is Professor of Anesthesiology at UC San Diego School of Medicine and Veterans Affairs Research Career Scientist with 20 years of experience testing gene therapies in neurodegenerative models. In 2012, he was bestowed the PECASE, the highest honour given by the United States Government to science and engineering professionals in the early stages of their careers.