Unlocking the Potential of Antibodies as a Therapy for Huntington’s Disease

The growth factorgrowth factor chemicals produced by the brain that help neurons to survive ‘BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD’ usually sends a “Survive!” signal to brain cells. In Huntington’s Disease (HD), this system doesn’t work as it should, so scientists have been looking for ways to boost the signal. Enter one of nature’s most useful tools: the antibody. Usually antibodies play an important role in the immune system, but researchers have identified two antibodies, produced by the company Pfizer, that can act like a set of spare keys to activate the TrkB receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to. This unlocks the door to determining whether a boost in TrkB activity is enough to prevent neuronsneuron Brain cells that store and transmit information from dying, in hopes of slowing the progression of HD.

Tipping the Survival Scale

Regular HDBuzz readers will be familiar with the brain molecule ‘BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD’, which we’ve described in past articles as a kind of ‘Miracle-Gro’ for the brain. This neurotrophic factor acts like a key, fitting into specific lock molecules found on the surface of brain cells. When BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD fits into one type of lock (a receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to called TrkB, pronounced “track-bee”), it acts as a sort of ‘protein life-coach’, causing a cascade of events that signal cells to survive or grow. Of course, things are a bit more complicated than that: BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD can also fit into a different ‘key-hole’, which sends out a “you can now die” signal instead. In HD, one thing is for certain—the balance between these signals is off. Research by Surmeier and his team suggests that this is due to an extra “you can now die” dose of BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD, in mice at least. There are also fewer TrkB receptors around in HD. So, researchers have been working on boosting the “Survive!” signal, and there is a plethora of evidence suggesting that more BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD seems to be better for neuronsneuron Brain cells that store and transmit information in HD.

So, can’t we just give HD patients more BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD?

Unfortunately, it’s not quite that simple. Like many drugs, when taken orally, not a lot of BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD makes its way to the patient’s brain. Perhaps more importantly, since BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD is a key that binds to more than one key-hole or receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to, we need to be careful about which signals are activated. To get around these limitations, researchers have been looking for other drugs that can act as a set of spare keys to unlock the TrkB receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to activity alone.

In a study published last year, Todd and colleagues took on the task of evaluating a number of contender drugs that have been recently reported in the literature, including the compounds ‘7,8-DHF’ and ‘LM22A-4’. In contrast to previous reports, the tested compounds did not activate the TrkB receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to or protect neuronsneuron Brain cells that store and transmit information against the harmful HD protein. However, two antibodies produced by Pfizer (captivatingly named ‘38B8’ and ‘29D7’), showed promise.

Repurposing nature’s tools

Antibodies are specialized proteins produced by the immune system to recognize unique features of a foreign target, such as a bacterium or virus. Our bodies naturally produce these molecules to seek out invaders and shut them down before they make us sick. Researchers across many fields have been repurposing these proteins for years—antibodies that recognize your favorite molecule make very useful tools! They have now generated antibodies that bind the TrkB receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to.

Todd and colleagues confirmed that the Pfizer antibodies ‘38B8’ and ‘29D7’ specifically bound to the TrkB receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to alone—a perfect lock-and-key fit. Once bound, these antibodies acted very much like BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD, although the response evoked by 38B8 and 29D7 was slightly lower than that of BDNFBDNF brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD. When tested in rat striatal neuronsneuron Brain cells that store and transmit information carrying the HD mutation, which had been grown in a dish, 38B8 and 29D7 reduced cell death. This is good news, as striatal neuronsneuron Brain cells that store and transmit information are the ones that are most affected in HD.

The next step these researchers are taking is to test whether 38B8 and 29D7 will actually work in an animal model of HD. But first they have the challenge of figuring out the best way to deliver the antibodies to the striatum.

So while these antibodies are still a long way from having direct therapeutic value in HD, this study has begun to unlock the potential of boosting TrkB signaling. It can also help answer questions about whether boosting the “Survive!” signal alone will be enough to prevent striatal neuronsneuron Brain cells that store and transmit information from dying in HD.

This study was also a good evaluation of other small TrkB-activating molecules. Research has been (sometimes frustratingly) described as 99% ‘re’ and 1% ‘search’: findings must be repeated and replicated to be trusted. Though not all of the drug candidates could be confirmed to work, the success seen with the antibodies provides a good basis for the future development of other small molecules that specifically and solely activate TrkB, and hopefully spare striatal neuronsneuron Brain cells that store and transmit information from the harmful effects of HD.

Learn more

• A Monoclonal Antibody TrkB Receptor Agonist as a Potential Therapeutic for Huntington’s Disease (open access)