Summary: Researchers have initiated the first-in-human Phase I clinical trial to evaluate the safety and feasibility of a gene therapy designed to deliver brain-derived neurotrophic factor (BDNF) directly to brain regions affected by Alzheimer’s disease and Mild Cognitive Impairment (MCI).
Source: UCSD
Researchers at the University of California San Diego School of Medicine have begun a first-in-human Phase I clinical trial testing a gene therapy intended to supply a critical growth protein to the brains of people diagnosed with Alzheimer’s disease (AD) or Mild Cognitive Impairment (MCI). This trial aims to assess both safety and early signals of therapeutic effect.
BDNF, or brain-derived neurotrophic factor, belongs to a family of neurotrophic growth factors that support neuron survival, encourage growth and differentiation of neurons, and strengthen synaptic connections. BDNF is especially important in brain regions that are vulnerable to degeneration in Alzheimer’s disease, including the entorhinal cortex and hippocampus—areas central to memory and learning.
Preclinical studies led by principal investigator Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine, demonstrated that delivering BDNF to these vulnerable brain regions prevented and reversed neuronal degeneration in animal models. Those studies reported restored connections and protection from ongoing cell loss in aged rats, aged monkeys, and genetically modified amyloid mice.
Amyloid mice are engineered to carry mutations in the amyloid precursor protein gene, which leads to formation of amyloid plaques—protein aggregates commonly associated with Alzheimer’s pathology. In humans with AD, BDNF levels are reduced in the entorhinal cortex, a region that typically shows early signs of disease-related dysfunction and contributes to short-term memory loss.
Because BDNF is a large protein that cannot cross the blood–brain barrier effectively, the research team will use a gene therapy approach. A harmless adeno-associated virus (AAV2) has been modified to carry the BDNF gene (AAV2-BDNF) and will be injected directly into targeted brain regions. The goal is for nearby cells to produce therapeutic levels of BDNF, restoring trophic support to degenerating neural circuits.
The surgical injections are precisely controlled and localized to minimize exposure to surrounding tissue. This targeted delivery is important because freely circulating or excessive BDNF can produce unwanted effects, including seizures; controlled, region-specific expression aims to maximize benefit while reducing risk.
This multi-year Phase I trial will enroll a total of 24 participants: 12 individuals diagnosed with either Alzheimer’s disease or Mild Cognitive Impairment who will receive the AAV2-BDNF treatment, and 12 comparative control participants monitored over the same interval. The primary aim is to evaluate safety and tolerability; investigators will also observe secondary outcomes related to biomarkers, imaging, and cognitive measures to detect potential signs of biological activity.
This trial marks the first human evaluation of AAV2-BDNF. Earlier gene therapy work, conducted between 2001 and 2012, tested AAV2 delivery of nerve growth factor (NGF) and showed evidence of increased growth, axonal sprouting, and activation of functional markers in participants’ brains. BDNF therapy is considered an advance for Alzheimer’s-related circuits because BDNF is a particularly potent growth factor for the entorhinal–hippocampal networks affected in AD and modern delivery methods aim to more effectively distribute the gene product in those regions.
Despite decades of research and substantial investment, current treatments for Alzheimer’s disease remain limited to a small number of symptomatic therapies; there is no cure nor an approved therapy proven to halt or reverse disease progression. Alzheimer’s disease affects millions of people and remains a leading cause of death, creating an urgent need for novel therapeutic approaches.
Gene therapy offers a different strategy from conventional drug development by enabling local, sustained production of therapeutic proteins within the brain. Investigators point to recent successes of gene therapy in other conditions—such as treatments for certain inherited retinal diseases and spinal muscular atrophy—as examples that reinforce the potential of gene-based approaches to treat neurological disorders.
BDNF gene therapy has the potential to do more than provide symptomatic relief: it aims to rebuild neural circuits, slow neuronal loss, and stimulate cell function. The research team looks forward to monitoring how this approach performs in patients with AD and MCI and to learning whether targeted BDNF expression can produce meaningful neuroprotective or restorative effects.
Note for potential subjects: For more information on this Phase I clinical trial, contact Michelle Mendoza at 858-249-3015 or email [email protected]
About this gene therapy and Alzheimer’s disease research news
Source: UCSD
Contact: Michelle Brubaker – UCSD
Image: The image is in the public domain
