10 Feb 2009

Could adeno-associated viruses bearing the gift of BDNF be the next biologic for treating Alzheimer disease? Time will tell, but preclinical data reported February 8 in Nature Medicine online suggest that the trophin by the name of brain-derived neurotrophic factor can reverse synapse loss, improve cell signaling, and restore learning and memory deficits in a variety of AD and aging models from cell culture to rodents and primates. “There are significant effects in preventing cell death and in influencing synaptic markers,” said Mark Tuszynski, University of California San Diego, La Jolla, who led the research. “Some of the earliest changes in AD occur with regard to synaptic connectivity. So if we have something that directly influences synapses, that can be intriguing from a therapeutic point of view,” he told ARF.

Tuszynski is co-founder of Ceregene, a private biotechnology company in San Diego that recently announced the start of Phase 2 trials of another neurotrophin, nerve growth factor (NGF), in AD. Ceregene’s other gene therapy product, neurturin for Parkinson disease, last fall stumbled in Phase 2 after promising data in Phase 1 (see ARF related news story).

On BDNF, Tuszynski noted that all its effects were manifest without any practical alterations in APP or amyloid. “From our perspective, this is a mechanism independent of APP that we can potentially use to target and influence neurodegeneration,” he said. In the interest of disclosure, he noted that Ceregene was not involved in the current study.

BDNF has been on the radar of AD research for some time. It is believed that in the entorhinal cortex and the hippocampus, regions of the brain that are hit hard and early in Alzheimer’s, levels of the trophin are lower in patients (see ARF related news story). That, plus the fact that the trophin has strong neuroprotective properties, led Tuszynski and colleagues to test if boosting BDNF levels could protect against the disease.

Joint first authors Alan Nagahara and David Merrill put BDNF through its paces in a variety of model systems. When they injected lentiviral vectors containing the BDNF gene into the entorhinal cortex (ERC) of six-month-old APP transgenic mice (J20 line) and then tested the animals one month later, they found that the treatment improved learning and memory. In both the Morris water maze test of spatial memory and a conditioned-fear paradigm, the treated animals performed better than transgenic controls and were statistically indistinguishable from wild-type animals. BDNF levels in the ERC were elevated after the injection, and the protein (tagged with green fluorescent protein) appeared in the CA1 and CA3 layers of the hippocampus. This was part of the strategy because ERC neurons project to those hippocampal layers, and BDNF is known to travel along the same route using anterograde transport. In the ERC, the treatment also improved Erk kinase signaling (a measure of trophic response), restored normal levels of the synaptic marker synaptophysin (synaptophysin is downregulated in J20 mice), and rescued altered gene expression found in the transgenic animals (as judged by whole genome array analysis).

The researchers tested a similar strategy in a rat model of normal aging, administering BDNF as a protein infusion into the medial ERC. Again, this improved age-related loss of learning and memory, restored Erk signaling to levels seen in younger rats, and partially rescued gene expression changes associated with aging. In primates, the researchers also found the trophin to be protective. When they gave BDNF-expressing lentiviruses to rhesus monkeys receiving a radiofrequency lesion of the perforant pathway linking the ERC to the hippocampus, the trophin protected the monkeys against loss of layer II ERC neurons. In the absence of the lentivirus, half of those neurons were typically lost, but 85 percent remained in the treated animals. In aged monkeys, too, the viral treatment was protective. Animals that received the treatment performed statistically better than age-matched controls in a visuospatial discrimination task designed to tax the medial frontal lobe. The researchers also cultured ERC neurons to show that BDNF can protect against Aβ toxicity; however, BDNF treatment of the APP transgenic mice had no effect on APP or amyloid load.

“This was a well-crafted study, to go across so many different models and especially to show the fact that the BDNF didn’t seem to impact amyloid deposition,” said Elliott Mufson in an interview with ARF. Mufson, from Rush University Medical Center, Chicago, studies neurotrophins in AD; he has collaborated with Tuszynski but not on this particular study. “This study fits nicely with the idea that it is time to think of alternatives to Aβ strategies,” added Mufson. Recently, Aβ-directed strategies have come under fire because of poor clinical trial results thus far, making some scientists think again about whether targeting Aβ is the best possible approach to find a therapy. Whether BDNF will represent a good alternative remains to be seen.

A BDNF therapy may be a long way off. “Currently, we are doing long-term dosing studies in animals. We want to see if long-term administration is safe,” said Tuszynski. There are many other challenges to this type of treatment, as well. Delivery, a key one, may have eased somewhat with the use of adeno-associated viruses; unlike adenoviruses, they evoke no strong immune response and are less prone to stop expressing the target gene after short intervals. Even so, problems remain in translating the approach to the clinic. Mufson said that the ERC is particularly difficult to target because of its size and location. And even when viruses can be targeted to the correct site, they often do not spread far enough from the injection site—a problem that surfaced in Ceregene’s latest neurturin trial (see ARF related news story). The initial Phase 1 trial of NGF in AD has shown promise (see ARF related news story), and according to Tuszynski, Ceregene is now recruiting 50 volunteers for a Phase 2 trial that will be conducted at eight centers across the U.S. as part of the Alzheimer’s Disease Cooperative Study (see press release). Analysis of that trial may help with the design of any future BDNF trials. (The eight trial centers and principal investigators are Case Western Reserve University, Alan Lerner; Emory University, Allan Levey; Georgetown University, R. Scott Turner; Mt. Sinai School of Medicine, Judith Neugroschel; Sun Health Research Institute, Marwan Sabbagh; University of Alabama at Birmingham, Ray Watts; University of California, Los Angeles, Joshua Grill; University of California, San Diego, Mike Rafii.)

One other benefit to BDNF therapy is that it might help with other diseases as well, particularly Huntington’s. The huntingtin protein appears to speed up intracellular transport of BDNF, a phenomenon that is blocked by mutant huntingtin (see ARF related news story). That these two proteins are intertwined is emphasized by a paper in the February 4 Journal of Neuroscience. Researchers led by David Rubinsztein at the Cambridge Institute for Medical Research, England, report that developmental problems of zebrafish embryos lacking either BDNF or huntingtin can be rescued by treating with only the trophin, suggesting that BDNF might be able to substitute for loss of normal huntingin in the disease. The authors suggest that “increasing BDNF expression may represent a useful strategy for Huntington disease treatment.—Tom Fagan

BDNF the Next AD Gene Therapy?

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