Therapeutics

AAV2-BDNF

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Overview

Name: AAV2-BDNF
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): MCI due to AD, Alzheimer's Disease
U.S. FDA Status: MCI due to AD (Phase 1), Alzheimer's Disease (Phase 1)

Background

This gene therapy uses an adeno-associated virus serotype 2 (AAV2) vector to carry a gene for human brain-derived neurotrophic factor into the brain. BDNF regulates neuron survival and function in key memory circuits in entorhinal cortex and hippocampus. In people with AD, BDNF is decreased. AAV2-BDNF attempts to restore normal levels of BDNF.

This program follows CERE-110, which attempted to deliver NGF via AAV (Mar 2018 news).

IIn early studies with mouse models of AD, BDNF gene therapy reversed synaptic loss, and restored learning and memory, without affecting amyloid plaque load (Nagahara et al., 2009; Nagahara et al., 2013). The same studies used rats and nonhuman primates to show that BDNF protein or lentivirus-BDNF delivered to the brain reduced age-related cognitive decline. Preclinical work with MRI-guided injection of AAV2-BDNF into the entorhinal cortex in nonhuman primates demonstrated elevation of BDNF protein in neurons of that region, and in the hippocampus, with no apparent safety issues (Nagahara et al., 2018; for review, see Tuszynski 2024).

Findings

In February 2022, Phase 1 began with an open-label study of this gene therapy in six volunteers with early Alzheimer’s, and six with mild cognitive impairment. Participants are to undergo one MRI-guided surgery to infuse AAV2-BDNF into the entorhinal cortex, followed by two years observation. Two doses are to be tested. Primary outcomes are the number of treatment-related adverse events, and memory changes measured on the Ray Auditory Verbal Learning Task and Benson Complex Figure Draw and Memory test. Secondary outcomes are change in FDG-PET, CSF biomarkers of amyloid, tau, and neurofilament, and MMSE ADAS-Cog. Sponsored by the University of California, San Diego, the study is underway there and at Ohio State University until October 2027.

Interim results were presented at the October 2024 CTAD conference. At that time, four subjects had safely completed gene delivery surgery. The first two received unilateral gene delivery to the right entorhinal cortex, and the other two were treated bilaterally. MRI confirmed accurate targeting and vector spread. No significant adverse events and no seizure activity were reported up to 15 months after treatment. In the first participant with FDG PET readings, the signal was increased by 14 percent on the treated side, and decreased in untreated regions. Surgical treatment of the AD patients will be complete in December 2024, and the MCI cohort is expected be completed in 2025.

For details on this trial, see clinicaltrials.gov.

Last Updated: 15 Nov 2024

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References

Therapeutics Citations

  1. CERE-110

News Citations

  1. NGF Gene Therapy Trial Data Published

Paper Citations

  1. Nagahara AH, Mateling M, Kovacs I, Wang L, Eggert S, Rockenstein E, Koo EH, Masliah E, Tuszynski MH. Early BDNF Treatment Ameliorates Cell Loss in the Entorhinal Cortex of APP Transgenic Mice. J Neurosci. 2013 Sep 25;33(39):15596-602. PubMed.
  2. Nagahara AH, Wilson BR, Ivasyk I, Kovacs I, Rawalji S, Bringas JR, Pivirotto PJ, Sebastian WS, Samaranch L, Bankiewicz KS, Tuszynski MH. MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates. Gene Ther. 2018 Apr;25(2):104-114. Epub 2018 Mar 13 PubMed.
  3. Tuszynski MH. Growth Factor Gene Therapy for Alzheimer's Disease. J Alzheimers Dis. 2024;101(s1):S433-S441. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

No Available Further Reading