It might be possible to treat a range of neurodegenerative conditions, including Alzheimer鈥檚 disease, with a one-time gene therapy that makes brain cells produce antibodies. Tests on human 鈥渕ini-brains鈥� growing in a dish show that these antibodies can reduce levels inside brain cells of the tau protein associated with these diseases.
鈥淲e鈥檙e looking at hopefully a 鈥榦ne and done鈥� approach,鈥� says at the Neural Stem Cell Institute, a non-profit organisation in New York state.
In several neurodegenerative conditions, abnormal levels of a protein called tau accumulate in brain cells and clump together to form what are known as tau tangles. Studies suggest that lowering the levels of tau inside cells can halt disease progression and even reverse some symptoms if done early enough.
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But lowering levels of a protein inside brain cells is extremely difficult. Almost all the tau-targeting treatments tested in people so far only affect tau protein outside cells, which might be why they haven鈥檛 proved effective.
One way to lower tau levels inside cells is to reduce production of the protein. This can be done with what are called antisense molecules, which bind to the messenger RNAs that carry the instructions for making tau proteins and stop them from being read.
Last year, a company called Biogen reported promising results from initial human trials of a tau-targeting antisense treatment called BIIB080. There were and scans showed a reduction in tau tangles. Further trials .
However, for antisense molecules to reach the brain, they must be injected into the cerebrospinal fluid, which involves a procedure called a lumbar puncture. And because the antisense molecules don鈥檛 last that long, people need regular lumbar punctures. This is a major disadvantage given the pain, cost and potential side effects of the procedure.
Butler鈥檚 approach is to instead get rid of excess tau using an intracellular antibody, or intrabody.
Normally, antibodies circulate in the blood, targeting pathogens like viruses. Intrabodies are modified versions of antibodies designed to bind to specific molecules inside cells.
Because antibodies are large proteins that can鈥檛 get through cell membranes, they must be made inside cells. This means using viruses to deliver DNA coding for intrabodies into cells. 鈥淲e deliver the intrabody as a gene therapy and then the cells will make the therapeutic,鈥� says Butler.
Neurons with the extra DNA will keep making intrabodies indefinitely, so the treatment is permanent.
Butler鈥檚 team has designed an intrabody that does two things. One section binds to the part of the tau protein that links up with other tau proteins to form tangles. This stops these proteins from adding to existing tangles.
The second section links up with structures called proteosomes that destroy damaged or excess proteins, resulting in the removal of the tau protein that the intrabody binds to. In other words, the intrabody drags tau proteins into the cell鈥檚 recycling bin.
In tests in human nerve cells and human brain organoids, or mini-brains, the team has shown that these intrabodies can reduce tau levels and improve survival of cells. While the intrabodies aren鈥檛 designed to directly target tau tangles that have already formed, Butler thinks that once tau levels have been reduced, cells are able to clear up the tangles themselves.
鈥淚ntrabodies would have advantages over current approaches,鈥� says at the University of Cambridge.
He agrees that reducing tau levels will probably clear up existing tau tangles. 鈥淸Antisense molecules] against tau work that way,鈥� says Goedert. But delivering the DNA coding for intrabodies to the brain is a major challenge, he says.
One worry, especially with an effectively permanent gene therapy, is that the treatment could work too well. Tau proteins have important roles in brain cells, so lowering tau levels too far could have adverse consequences. For this reason, Butler鈥檚 team has developed variants of the intrabody with differing levels of effectiveness.
鈥淲e鈥檝e developed this controlled degradation where we can set the level of clearance to a desired level,鈥� says Butler.
Animal studies are now getting under way and Butler hopes human trials could begin in two or three years if all goes well.
Other teams are working on similar therapies. One related approach is to add the cellular equivalent of 鈥渞ecycle me鈥� labels to tau proteins, for instance. But Butler says these labelled tau proteins can still end up in tangles.
He thinks it is more effective to deliver tau proteins directly to recycling bins, rather than relying on cells to do it. 鈥淚t鈥檚 a very simple and clean approach.鈥�
bioRxiv
