Interview with Tetraneuron | ReGenAD: Alzheimer’s Therapy
Tetraneuron is advancing ReGenAD, a clinical research project supported through the Public-Private Collaboration Projects 2025 programme of the Agencia Estatal de Investigación (AEI). Developed together with Fundación HM Hospitales and Fundación CIEN, the project aims to bring TET-101, an innovative gene therapy for Alzheimer’s disease, to its first evaluation in humans, with a particular focus on patients with moderate Alzheimer’s disease.
We spoke with the ReGenAD consortium to learn more about the scientific and clinical challenges behind the project, how TET-101 is designed to act on different mechanisms involved in neurodegeneration, and what this first-in-human study could contribute to the future development of gene therapies for Alzheimer’s disease.
1. What clinical need led TETRANEURON to develop TET-101, and why is it particularly important to find new alternatives for patients with moderate Alzheimer’s disease?
Alzheimer’s disease continues to represent one of the major unmet medical needs in neurodegenerative diseases. Although important advances have been made in recent years, therapeutic options capable of modifying the course of the disease remain limited and are mainly focused on the early stages of the disease.
At TETRANEURON, we believe it is particularly important to explore new alternatives for patients with moderate Alzheimer’s disease, a population in which cognitive and functional decline already has a significant impact on patients’ independence and their surrounding environment, and for whom therapeutic options are particularly limited.
TET-101 was developed precisely in response to this need: to develop a different therapeutic approach targeting cellular mechanisms involved in the disease, with the potential to act on several of the biological processes that contribute to its progression.
2. What differentiates the TET-101 approach from current treatments and other strategies targeting specific mechanisms such as amyloid or tau protein?
One of the main differences of TET-101 is that it is not designed to act exclusively on a single pathological feature, such as the accumulation of beta-amyloid or tau. Our approach is based on the idea that Alzheimer’s is a multifactorial disease in which alterations in different cellular processes occur simultaneously.
TET-101 uses gene therapy to modulate E2F4 activity through a modified variant, E2F4DN, with the aim of acting on cellular mechanisms that may be altered during the disease.
It is therefore a potentially complementary approach to strategies specifically targeting amyloid or tau. Rather than directly eliminating a specific pathological protein, we aim to intervene in broader cellular mechanisms associated with the way cells respond to the disease.
3. What role does E2F4 play in Alzheimer’s disease, and why did you decide to target this mechanism through gene therapy?
E2F4 is a transcription factor involved in the regulation of numerous cellular processes. Our preclinical research has identified alterations related to its activity in the context of Alzheimer’s disease and has provided the basis for studying its modulation as a potential therapeutic strategy.
TET-101 incorporates a modified form of E2F4, known as E2F4DN, designed to maintain E2F4 activity under conditions in which its function is altered, promoting the restoration of neuronal homeostasis. Studies carried out by TETRANEURON and its collaborators have shown that this strategy can act on different processes involved in neurodegeneration, including synaptic dysfunction, neuroinflammation, neuronal loss and alterations related to cellular homeostasis, helping to preserve or restore neuronal function.
Gene therapy is particularly interesting in this context because it makes it possible to stably introduce the genetic information required to express E2F4DN in neurons. This opens up the possibility of achieving a prolonged effect following a single administration, something particularly relevant in a chronic neurodegenerative disease such as Alzheimer’s.
4. Which results from the preclinical studies have been key to moving towards the first evaluation of TET-101 in patients?
The preclinical development of TET-101 has included pharmacological studies in rodent models of Alzheimer’s disease, together with an extensive biodistribution and safety programme in a non-rodent species.
In mouse models of Alzheimer’s, we have observed favourable effects on functional parameters related to memory, including improvements in hippocampal-dependent memory tests. These results have also made it possible to explore different dose levels and characterise the range of pharmacological activity.
In parallel, studies carried out in a non-rodent species have enabled us to characterise the distribution of TET-101 following administration into the central nervous system and to assess its safety. The vector reached relevant regions of the brain, and toxicology studies showed a favourable safety profile at the doses evaluated.
Taken together, the pharmacological evidence obtained, along with the biodistribution and safety data, has provided the preclinical basis required to move towards the first evaluation of TET-101 in patients.
5. What will be the objectives of the first clinical trial of TET-101, and what information do you expect to obtain about its safety, tolerability and potential biological effects?
As this will be the first administration of TET-101 in humans, the primary objective of the trial will be to assess its safety and tolerability and characterise the behaviour of different dose levels.
In addition, the study will include a broad evaluation of clinical and biological parameters, which will allow us to obtain the first indications of the treatment’s potential effects. The cognitive and functional evolution of participants will be assessed, and biomarkers in cerebrospinal fluid and blood will be analysed alongside neuroimaging techniques and neurophysiological assessments.
It is important to emphasise that this is an initial study and is therefore not designed to demonstrate clinical efficacy. However, integrating safety data with clinical measures, biomarkers and imaging techniques will provide highly valuable information to determine whether there is evidence of biological activity and to guide the next stages of clinical development.
6. What value does the collaboration between TETRANEURON, Fundación HM Hospitales and Fundación CIEN bring to advancing TET-101 from preclinical development to evaluation in patients?
Developing a gene therapy for a disease as complex as Alzheimer’s requires the integration of very different capabilities. The collaboration between TETRANEURON, Fundación HM Hospitales and Fundación CIEN brings together expertise in advanced therapy development, clinical research, neurology and the specialised assessment of patients with neurodegenerative diseases.
For us, this type of collaboration is essential because it connects the scientific and technological development of TET-101 with the clinical expertise required to design its evaluation in patients rigorously.
ReGenAD provides precisely a framework for integrating these capabilities and facilitating the transition from preclinical research to clinical development, while always maintaining patient safety and the generation of high-quality scientific evidence as priorities.
7. If ReGenAD achieves its objectives, what would this project mean for the future development of TET-101 and gene therapies targeting neurodegenerative diseases such as Alzheimer’s?
ReGenAD represents an important step in advancing TET-101 towards clinical evaluation and generating the evidence required to continue its development.
If the results support its safety and provide consistent signals of biological activity, they would make it possible to define the next stages of the clinical programme more precisely, including aspects such as dose selection and the most appropriate variables for future studies.
From a broader perspective, the project may also contribute to generating knowledge about the application of gene therapy in complex neurodegenerative diseases. Alzheimer’s presents very different challenges from the monogenic diseases in which much of gene therapy was initially developed. Demonstrating that these technologies can be used to modulate relevant biological mechanisms in multifactorial diseases would open up new possibilities for research and development in this field.
8. How has your experience been working with Evolution Europe during the ReGenAD funding process? What would you highlight as the distinctive value of the collaboration?
Our experience working with Evolution Europe during the application process for ReGenAD has been very positive. Their support enabled us to structure a complex scientific and clinical project so that its objectives, impact and development plan were clearly reflected in the proposal.
We would particularly highlight their ability to understand the specific characteristics of a biotechnology and gene therapy project and translate them into the specific requirements of funding programmes. The combination of knowledge of the European funding ecosystem, coordination capabilities and support throughout the entire process has been particularly valuable to us.
