Post by Anastasia Sares
What's the science?
The Huntingtin (HTT) gene has a number of roles in our brain, including neural development and transport of neuronal cell components, and we still don’t understand everything about it. We do know that the gene has an area where the base pairs “CAG” repeat a number of times. Sometimes, during DNA replication, the “CAG” gets stuck on repeat: if there are over 35 repeats, this leads to Huntington’s disease. The more repeats, the earlier the onset of symptoms, which include chorea (dance-like movements), muscle rigidity, lack of coordination, dementia, and depression. Statistically, 50% of the children of a person with Huntington’s will also have the disease.
In the mere 25 years since the discovery of the gene causing Huntington’s disease in 1993, there are now a myriad of possible approaches to treat this devastating genetic disease. This week in Neuron, Tabrizi and colleagues inventoried different treatment options for Huntington’s disease at the DNA, RNA, and protein level, showing how far in clinical trials each one has progressed, and evaluating their pros and cons.
What do we know?
In our body’s cells, genetic material (DNA) lives in the nucleus. In order to make functional proteins that do work in the rest of the cell, the DNA must first be transcribed into RNA, a messenger that takes the instructions outside of the nucleus, and then translated into proteins. The many repeats of “CAG” base pairs in the mutant HTT gene get translated into a long chain of abnormal material in the resulting protein. Because of HTT’s integral role in cell, these bad proteins have a variety of different effects, not least of which is that they can fragment off and cause neurofibrillary tangles. The tangles may lead to cell death in important brain regions like the striatum, which is responsible for movement selection and initiation.
When it comes to treating the disease, there are many different plans of attack. It might be possible to directly modify the mutant Huntingtin gene itself, chopping it out of the DNA. We could also target RNA, the messenger. Finally, we could intervene at the level of the Huntingtin protein, breaking down the mutants before they have a chance to affect other parts of the cell. However, silencing HTT, especially early in life, can cause a host of problems. A successful therapy must either silence ONLY the mutant HTT, or find a balance between reducing mutant HTT and leaving enough normal HTT for successful neural development. There’s another problem, too. Because of the mutations in the HTT gene, the cell doesn’t always follow the normal rules about where it should start and stop in the process of creating RNA or proteins. This can result in a number of non-standard proteins which are also toxic. An optimal therapy would be able to remove or reduce these non-standard proteins.
To make a treatment acceptable for use in humans, the method must first be demonstrated to be effective in cell cultures, other mammals, and non-human primates. It then proceeds to rigorous multi-phase clinical testing. Recent advances in DNA technologies like the CRISPR/Cas9 system allow for precision manipulation of DNA, and go directly to the source of the problem for a one-time treatment (this means the non-standard proteins will be taken care of as well). However, these technologies are very new and are still in the preclinical stage. Most DNA treatments, including CRISPR/Cas9, and also some RNA treatments, are currently very invasive, requiring insertion of foreign viral proteins directly into the brain. This is irreversible and might provoke inflammation or other immune responses, not to mention the high risks of brain surgery in general.
The most clinically advanced treatments for Huntington’s disease are RNA-targeting methods, especially antisense oligonucleotides (ASOs). Unlike the highly-invasive DNA treatments, ASOs can be administered via lumbar puncture. However, ASOs might have to be administered repeatedly, which isn’t ideal, and they can’t target all of the abnormal proteins generated by the mutant HTT gene. At the protein level, one therapeutic method would be to stimulate the cell’s native machinery to degrade mutant Huntingtin proteins faster (through PROTACS). However, this is also preclinical and needs to be developed further, as we don’t yet know the best way to deliver them to the central nervous system or what side effects they might have. No matter which method is chosen, silencing both normal and mutant HTT seems more promising since it won’t have to be as personalized for patients with different numbers of CAG repeats. However, if we are to decrease HTT on a system-wide level, the timing of the intervention is critical. It would be important to delay start time of the therapy to avoid the period of neural development but also start treatment early enough for it to be effective. Having better detection methods for Huntington’s disease progression will be crucial to this endeavor.
What’s the bottom line?
The principles behind Huntington gene therapies also extend to many other genetic diseases. The main problem is how to successfully deliver these therapies. The most powerful and specific therapies are also the most invasive and dangerous, and editing DNA comes along with ethical concerns. There is still much work to be done in bringing these therapies to the clinic, and future research will need to focus on providing a safe delivery of therapies while mitigating harmful side effects.
Tabrizi et al. Huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron (2019). Access the original scientific publication here.