A first-class clinical trial to evaluate gene therapy for Alzheimer’s disease

Researchers at the University of California San Diego School of Medicine have launched a first-stage Phase I clinical trial to evaluate the safety and effectiveness of gene therapy to deliver key proteins into the brain of people with Alzheimer’s disease (AD) or mild Cognitive Damage (MCI), a condition that often precedes full-blown dementia.

The protein, known as brain-derived neurotrophic factor or BDNF, is part of a family of growth factors found in the brain and central nervous system that support the survival of existing neurons and stimulates the growth and differentiation of new neurons and synapses. BDNF is particularly important in brain regions prone to AD degeneration.

In previously published research, lead researcher Mark Tuszynski, MD, PhD, professor of neuro-science and director of the Institute of Neuroscience Translation at UC San Diego School of Medicine, and colleagues described the prevention and reversal of dementia brain cells and death in animal models.

“We found that it was possible to deliver BDNF to the part of the brain affected earlier in Alzheimer’s disease – the entorhinal cortex and hippocampus – able to reverse the loss of connections and protect against cell degeneration ongoing, “Tuszynski said. “These benefits have been observed in elderly rats, old monkeys and amyloid mice.”

Amyloid mice are genetically engineered to detect a mutation in the gene encoding the precursor amyloid protein, thereby developing amyloid plaques – clusters of undigested proteins in the brain that are regarded as a distinctive feature of AD.

BDNF is usually produced throughout life in the entorhinal cortex, an important memory center in the brain and one of the first places where the effects of AD usually manifest in the form of short-term memory loss. People with AD have reduced BDNF levels.

But working with BDNF is not easy. It is a large molecule and cannot pass through a blood-brain barrier. As a result, researchers use gene therapy in which a harmless adeno-associated virus (AAV2) has been modified to carry the BDNF gene and introduce it directly into targeted areas of the brain, where researchers hope to promote therapeutic BDNF in nearby cells.

The injections are closely controlled to include knowledge of surrounding degenerating neurons as free circulation of BDNF can cause adverse effects, such as seizures.

The three-year trial employs 12 participants with AD or MCI who have been confirmed to receive AAV2-BDNF treatment, with a further 12 serving as comparative controls over that period.

This is the first safety and efficacy evaluation of AAV2-BDNF in humans. A previous gene therapy trial from 2001 to 2012 using AAV2 and a different protein called zero growth factor (NGF) found elevated growth, axonal sprouting and activation of action signals in participants ’brains.

“The BDNF gene test in AD represents an improvement over the earlier NGF test,” Tuszynski said. “BDNF is a more potent growth factor than NGF for degenerative neural circuits in AD. In addition, new ways of delivering BDNF deliver and distribute it into the entorhinal cortex and hippocampus. “

Despite billions of dollars of research investment and decades of effort, there are only two symbolic treatments for AD. There is no approved treatment or method to prevent or stop the progression of the neurological disorder that affects more than 5 million Americans and is the sixth leading cause of death in the United States.

A number of clinical trials are underway to evaluate pharmacokinetics. Tuszynski said that gene therapy, which ended in 1980 and was tested on a number of diseases and conditions, represents a different approach to disease that requires new ways of thinking about the disease and new attempts at it. remedies.

“We hope to build on the recent success of gene therapy in other diseases, including progressive success in the treatment of congenital weakness in infants (spinal muscular atrophy) and blindness (Hereditary Leber Optic Neuropathy, a type of retinitis pigmentosa), “said Tuszynski.

“BDNF gen therapy, unlike other AD therapies currently being developed, has the potential to rebuild brain circuits, slow cell loss and stimulate cell activity. We look forward to see the impact of this new effort in patients with AD and MCI. ”

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For more information about this Phase I clinical trial, contact Michelle Mendoza at 858-249-3015 or email [email protected]