Breakthroughs in ALS Treatment: Importance of Brain health, Drugs and ALS Research
- EverythingALS Editorial
- May 15
- 8 min read
Introduction:
While comprehensively analyzing the diagnostic approaches and treatment for ALS, brain health plays a very significant role in decoding the gradual progression of the disease. Amyotrophic Lateral Sclerosis (ALS) is a complex and devastating neurodegenerative disease that primarily targets motor neurons, leading to progressive loss of voluntary muscle control. Despite decades of research, its precise mechanisms and effective ALS treatment strategies remain elusive. Here are some insights on some of the most pressing questions surrounding ALS, ranging from selective neuronal vulnerability and the role of upper motor neurons, to updates on promising treatments like NU-9 and Tofersen. This further delves into emerging concepts such as prion-like transmission, brain-computer interfaces, personalized medicine, and the potential of neuroplasticity in late-stage ALS.
Featured Questions
1. Why aren’t sensory neurons impacted in ALS?
Not all neurons will be impacted in all diseases. ALS primarily affects the motor neuron circuitry due to selective vulnerability and differences in gene expression and function between motor and sensory neurons. Sensory neurons have distinct molecular profiles and are not part of the motor circuitry targeted in ALS. Other diseases (e.g., sensory neuropathies) specifically affect sensory neurons, highlighting this selectivity. As the disease progresses further, the sensory neurons might become affected, but the primary impact remains on the motor neuron circuitry.
2. What is the relationship between upper motor neurons (UMNs) and non-motor neurons?
There are many types of non-motor neurons, such as callosal projection neurons, which are also excitatory, similar to pyramidal neurons. Although they are smaller than corticospinal neurons, they are born at the same time, migrate together, and reside typically in layers 1 or 2. In ALS, the callosal projection neurons remain relatively healthy but corticao-spinal neurons feel the burden. The reason could be due to the projection field, as the callosal projection neurons project to the other side of the cortex while corticospinal neurons go to the spinal cord. Differences in gene expression profiles may also play a role.
UMNs integrate inputs from diverse non-motor neurons (e.g., excitatory, inhibitory, sensory) to initiate voluntary movement. While ALS primarily targets motor neurons, non-motor neurons (e.g., cortical interneurons) may contribute indirectly to UMN dysfunction as the disease progresses.
3. Recent updates on the development and experimental testing of NU9?
There are on-going investigations on ALS models along with ALS FTD and Alzheimer’s disease models. With the funding from the Cure SPG foundation, the team is studying various pre-clinical models of several diseases and analyzing how specific compounds may help address their underlying causes.
4. A case-related question – “A’s mother currently has ALS, and her aunt has dementia. The mother’s uncles died of Alzheimer’s, Parkinson’s, and dementia. A is also diagnosed with ALS and does not yet have the results of the SOD1 test. A wants to use QALSODY for treatment immediately to avoid wasting any time. If SOD1 test results are negative in the future, can this drug potentially cause any harm if A does not have any genetic inheritance?
Firstly, it is important to consult clinicians and doctors before beginning any treatment. Tofersen is an ASO with anti-sense oligonucleotide designed to silence the mutation. If A does not have this mutation, there’s nothing to target and the treatment may not be effective.
5. What is the potential for Tofersen to stabilize ALS and potentially reverse it? Are there any records of the undoing of ALS, stabilization or reversal?
Tofersen was given approval after a 60-day clinical trial. However, the nature of the disease and its impact needs to be gauged better, and given further evaluation from experts.
6. What about prion-like transmission?
There are several studies indicating prion-like transmission, especially in the context of mutated proteins. For instance, if the protein has one mutation, it introduces a kink and the structure of the protein changes. When this mutated protein interacts with another wild protein, it also becomes mutated, even though there was no specific mutation. The reason – one of them has structural change. This causes a chain reaction, impacting other proteins. According to several theories, the SOD1 mutation may have a prion-like progression or some kinds of TDP pathologies. Theoretically, it could be possible. Also, the location of the mutation is also important because not all mutations are the same. With the SOD1 gene, how many mutations have been detected, for example, 89, 90 or 100, as there is not a single mutation, but multiple mutations. The same is also true for TDP, and the location is also important.
7. How would you place the sensor array in a brain computer interface? Would more than one site be better?
There are ongoing tests for several cases, where the sensors are placed in the motor cortex to modulate, excite, or read and transmit brain’s activity together with another edit machine or reader. Furthermore, one of the problems in ALS is degeneration of apical dendrites. When the degeneration is to the extent that apical dendrites don’t receive input, the sensors are positioned in the surface over the cell body and deep layers, making it harder for them to respond to each other. Healthy apical dendrites are essential. Modulation would be more effective at the early stages of the disease as opposed to the later stages of the disease. Some of the brain computer interfaces are biodegradable and some of them may be transplanted. There are ongoing studies conducted on large mammals, including primates, focusing on the vertical placement into the motor cortex.
8. Currently, is there any way to determine the underlying cause of the disease of ALS?
Every patient’s serum and plasma can be subjected to proteomic, lipidomic, RNA sequencing and metabolomic tests and used for ingenuity pathway analysis or large data management toolboxes. The data can be compiled to further determine the upstream regulator, the converging path, the canonical pathway, and gradually, the main cause. Each patient carries the relevant information within them, based on findings in the serum, plasma, CSF, urine or other biological fluids. It is important to not only compile the data, but also derive insights from this data to inform our understanding of ALS. For example, if someone has gene ABC up down, and gene ABC and D are working together on the axon transport pathway, there would be three genes that are upregulated, downregulated, but they are all in the axon transport pathway. This can signify that the axon pathway may be the most affected. There is a rising need to develop personalized medicine approaches for the disease.
9. Oncology routinely uses multiple compounds to treat all the different types of cancers. How about the potential of combining NU-9 and Riluzole and an immunomodulator for treatment purposes?
Yes. The field of cancer research is ten years ahead of neuroscience. There is awareness about selectivity and different tumors based on cell-type specificity. Cancer research is forming a strong prototype for neuroscience solutions. In the current landscape of medical research and FDA drug development, the cure is not focused on specific diseases like Alzheimer’s or Parkinson’s, but instead on the mechanism that drove disease progression, with the goal of overcoming the burden of mechanistic dysfunction. For example, clinical trials are conducted to improve the health and integrity of mitochondria. If XYZ is the best mitochondrial drug discovered in the process trials would enrol patients whose disease developed through mitochondrial dysfunction. This is a game-changer as we understand that ALS is a heterogenous disease, unlikely to be cured by one single drug. Researchers are recognizing that only specific subpopulations, sometimes as small as 10-20 people, may benefit from a given treatment.
10. Have studies determined if NU-9 has any effect on neurofilaments or if its clinically significant?
Within the ongoing research, NU-9 has been administered to SOD1 mice and TDP mice for a period of 60 days. Then, the brain is isolated for specific tests like proteomics, and the plasma from the blood is collected to analyze changes following treatment. In addition to neurofilaments, there are many other proteins that come up. Pro-neuro filaments are important, but especially when it comes to motor neurons, other proteins come up as well.
11. Can this protein help with UMNs that already have been damaged? Is there any reversal that’s possible?
The treatment process was started at P60 or postnatal day 60, which is a specific time when these mice models begin to show symptoms. Furthermore, with P60, it is possible to detect that at the cellular level, a significant amount of corticospinal motor neurons are already degenerated, and the degeneration process is ongoing. Generally, it is assumed that death happens overnight, but in reality, death is a process. Everyday, we are dying by one more day, and neurons which are vulnerable to degeneration feel the complete burden in the process leading to death. But, once the underlying issues are addressed, neurodegeneration is either slowed or stopped, providing an opportunity to contemplate the path of neurodegeneration and opt for the pathway of neuro-integration. With a 60-day treatment, the ongoing neurodegeneration can be changed to neuro-integration by resolving issues in the process.
12. How can the community support ALS research?
Community building is really important and attending meetings like the Expert Talks is also really important. Fellowships can help us to train the young generation of scientists. Furthermore, networking with key philanthropists or drug companies who are interested in this research is helpful.
13. Is there anything we should be eating to maintain the health of our neurons?
Typically, problems with sleep are very common in patients with neurodegenerative diseases. So, maybe, to help ourselves, we really need a good amount of sleep, because the brain secretes all the toxins and dirt into the biological fluid, CSF, which is cleaned during sleep. The human body has around 850 ml of CSF. During sleep, the heartbeat becomes regular and the CSF is cleaned. When the person does not have good quality sleep, or has sleep apnea, then the CSF is not cleaned. When the CSF is not cleaned for 5 years, 9 years, 10 years etc., it leads to protein accumulation, sporadic cases of neurodegeneration, and no mutation. So, to keep our brain healthy, we have to sleep well, as it will help the brain take a deep breath and function better. Also, oxygen levels must be high, which is helped by exercise.
14. Even in a patient with complete loss of function, not all motor neurons are lost and the remaining ones can take over the function of the others. This idea was based on a few patients who have recovered on their own. Considering the concept of neuroplasticity, can AKV-9 have an effect on a patient who’s completely lost their functions? Are there any ongoing investigations about neurofilament biomarker improvements with AKV9?
There must be experiments conducted in such a way that the treatment begins at P-90 or at a different time point, exploring how late we can go to see the effect. However, at present, there are very few studies on this subject. The role of neurofilaments needs to be further explored in clinical trials, with Phase 2 studies offering a deeper investigation.
Conclusion:
The insights shared during the Expert Talk underscore the multifaceted nature of ALS and the growing importance of a personalized, multi-pronged approach to treatment. Advances in molecular profiling, brain-computer interfaces, and targeted therapies such as NU-9 and Tofersen highlight the potential to not only slow disease progression but, in some cases, to reverse damage and support neuronal recovery. The community’s role—through advocacy, research funding, and public awareness—remains crucial in accelerating these breakthroughs. While challenges persist, the combination of scientific innovation, cross-disciplinary collaboration, and patient-centric care continues to drive the field forward, offering renewed hope for meaningful change in the treatment and understanding of ALS.
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