STEM CELLS FOR ALS/MND TREATMENT

Stem cells are the first cells of our body, with the ability to form an entire multicellular individual. At each stage of development, they lose their strength limited to their surroundings. This exclusive ability of certain types of stem cells to form all other body cells is recognized as a new method to treat various degenerative conditions that are conventionally declared to be incurable. Thus, it is possible to slow down or delay the progression with the help of stem cells for ALS, if not stopped completely.

The primary response from clinical and preclinical studies has supported the fact that stem cells replace dying neurons with new ones; and promote the differentiation potential of residential stem cells, present in the niche of the brain.

The treatment approaches are modified based on the number of cells to be delivered at the site, and different combinations of cells to be used for better treatment outcomes. Other studies are also focusing on a combined treatment option offering mesenchymal stem cell-derived exosomes as a delivery tool to provide growth factors and other trophic factors, which in turn promotes the formation of new, healthy neurons.

However, it is important to understand that the treatment outcome may depend upon several factors:

Type of stem cells used for infusion: As discussed above, stem cells lose their potential at each stage of development. Accordingly, with the available stem cell types, mesenchymal stem cells are identified to be the most potent cells, with the ability to form neurons; while hematopoietic stem cells isolated from bone marrow and/or peripheral blood are only limited to become cells of blood origin.

The source of stem cells: The number of stem cells infused in the body is a decision-maker in therapeutic outcomes. Various studies have suggested that the number of stem cells should be in proportion to the body weight and age of the person. Thus, before opting for stem cell treatment for ALS, one should be aware of the number of stem cells to be infused into the body. Further to which, in the current laboratory setting, mesenchymal stem cells isolated from umbilical cord Wharton’s jelly is the abundant source of stem cells, which is easily accessible and ethically exempted. Whereas other available sources of stem cells like bone marrow and adipose tissue contain only 0.01% of mesenchymal stem cells out of other cell populations.  

The Extent of Motor Neuron Degeneration: While experts are referring to stem cell therapy as a protective strategy for ALS/MND; they have clearly stated that “It is everything about timings; if a majority of the motor neurons are dead, no matter how many stem cells and exosomes are infused, they have got nothing to act on”! Thus, it is important to intervene early in the disease progression, and that’s when the progression will be delayed.

In a conventional setup, no effective treatment strategy is available for ALS. The entire focus is on minimizing mortality. Effectively only two drugs are approved by the US FDA, edaravone and riluzole; which are offered to prolong the lifespan of the person; however, none of them are proven to be effective at the cellular level, restoring lost neuronal function¹. The statistical data analysis further confirmed that other supportive therapies, as possible treatment options for motor neurone disease, will help achieve smaller milestones.

For instance, 75% of people with ALS experience early-onset limb weakness, and hence require physiotherapy to relieve physical symptoms². While 25% of the people experience bulbar dysfunction, along with other common issues like dysarthria, dysphagia, muscle twitching, weakness, etc.; and hence, early speech therapy and nutritional support have proven to be beneficial for them². Other specific symptoms like muscle spasticity, muscle twitching, etc. can be treated with the help of steroidal drugs like cannabinoids, baclofen, tizanidine, etc. At the same time, people with emotional lability can offered medications like benzodiazepine, quinidine sulfates, serotonin uptake inhibitors, etc³.

However, one should also note that in the past half-century, more than 50 randomized controlled trials were performed, to propose the efficacy of these disease-modifying drugs⁴. However, these studies failed to demonstrate positive results, further highlighting the need to extensively understand the underlying mechanism and propose a treatment that can hit at the cellular level. With advancements in stem cells for ALS research, many studies are conducted worldwide to assess the efficacy of stem cell treatment for motor neurone disease.

Thus, cellular therapy has proven to be a new hope for ALS treatment, which targets multiple pathogenic mechanisms including neuroinflammation⁵. Although, studies demonstrated the efficacy of treating ALS with the help of embryonic stem cells; their usage is prohibited due to ethical and safety concerns⁶; while induced pluripotent stem cells, earlier believed to be the potent candidate, seem to be problematic due to their cancerous properties⁷.

Thus, in the current available set-up, mesenchymal stem cells for Motor Neurone Disease are the most promising cellular therapy tool, due to the following reasons⁸:

• Mesenchymal stem cells can be safely and effectively obtained and cultured at a larger scale from body tissues.
• These cells can migrate at the site of injury, an exclusive property of stem cells called “homing” that is regulated by growth factors and cytokines.
• These cells can develop neuronal phenotypes under appropriate conditions.
• They can release various tropical factors to facilitate nervous tissue maintenance and repair.
• These cells do not have any ethical concerns as compared to their other counterparts.
• They can be safely administered without the risk of immune rejection.
• MSC-derived exosomes are well assessed for their potential to create a supportive microenvironment.

References

1. Saitoh Y., Takahashi Y. (2020). Riluzole for the Treatment of Amyotrophic Lateral Sclerosis. Neurodegenerative Dis. Manag. 10, 343–355. 10.2217/nmt-2020-0033
2. Hobson E. V., McDermott C. J. (2016). Supportive and Symptomatic Management of Amyotrophic Lateral Sclerosis. Nat. Rev. Neurol. 12, 526–538. 10.1038/nrneurol.2016.111
3. Masrori P., Van Damme P. (2020). Amyotrophic Lateral Sclerosis: a Clinical Review. Eur. J. Neurol. 27, 1918–1929. 10.1111/ene.14393
4. Petrov D., Mansfield C., Moussy A., Hermine O. (2017). ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment? Front. Aging Neurosci. 9, 68. 10.3389/fnagi.2017.00068
5. Mitsumoto H., Brooks B. R., Silani V. (2014). Clinical Trials in Amyotrophic Lateral Sclerosis: Why So many Negative Trials and How Can Trials Be Improved? Lancet Neurol. 13, 1127–1138. 10.1016/S1474-4422(14)70129-2
6. Lo B., Parham L. (2009). Ethical Issues in Stem Cell Research. Endocr. Rev. 30, 204–213. 10.1210/er.2008-0031
7. Yamanaka S. (2020). Pluripotent Stem Cell-Based Cell Therapy-Promise and Challenges. Cell Stem Cell. 27, 523–531. 10.1016/j.stem.2020.09.014
8. Karussis D., Karageorgiou C., Vaknin-Dembinsky A., Gowda-Kurkalli B., Gomori J. M., Kassis I., et al. (2010). Safety and Immunological Effects of Mesenchymal Stem Cell Transplantation in Patients with Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Arch. Neurol. 67, 1187–1194.

Amyotrophic Lateral Sclerosis also known as motor neuron disease or Lou Gehrig’s Disease is a relatively fatal neurodegenerative disease.  It was originally known as Charcot's disease, after the scientist Jean-Martin Charcot, who discovered it for the first time in 1869.

The disease is characterized by the progressive degeneration of motor neurons from the central nervous system, causing functional damage. Since motor neurons regulate voluntary movements in the human body, a person with ALS can progressively lose the ability to speak, eat, move, or even breathe in the later stage of his life.

Statistics have emphasized that currently every 90 minutes, someone is getting diagnosed with ALS, and someone is passing away from it. Many people reported with ALS are in the age group of 40 to 70 years, with an average diagnostic age of 55 years. However, there are certain reported cases in people in their twenties or early thirties as well. Also, it is more common in men than in women, however with increasing age, its occurrence is common in both men and women.

Although there is no quick test available, that can diagnose ALS comprehensive diagnosis and management of motor neurone disease is suggested for accurate detection:

Electrodiagnostic Testing: It is one of the critical tests performed to diagnose ALS. The test is further  categorized as electromyography (EMG) and nerve conduction study (NCS). These tests are further helpful in assessing peripheral nerve damage and muscle wastage, associated with ALS.

Magnetic Resonance Imaging Technique: It is advanced imaging technology to detect structural abnormalities in the motor neurons, causing muscle wastage. It may also be helpful to detect the extent of muscle wastage.

Biopsies: Muscle or nerve biopsies are obtained from the lumbar puncture; the tissues can be visualized under the microscope to detect structural abnormalities. Similarly, with the help of a special spinal needle, the pressure in the spinal canal and the brain is detected to understand the extent of functional damage.

Gut Microbiome Analysis: A growing evidence based on the studies so far, suggests that the gut microbiome actively contributes to the pathogenesis of ALS. Thus, systemic analysis of gut microbiomes at the molecular levels may be helpful in the early detection of ALS.

Genetic Tests: Certain forms of ALS are associated with many genetic mutations. Thus, understanding genetic abnormalities that are characteristic of the ALS is helpful for individuals, known to have a family history of ALS.

Overall, the progression of ALS is measured with the help of the King’s staging system. The grading scale includes

• Stage 1: Symptomatic onset with involvement of upper or lower limb area
• Stage 2A: Diagnosis
• Stage 2B: Involvement of the second region
• Stage 3: Involvement of the third region
• Stage 4A: Need of gastrostomy
• Stage 4B: Need for non-invasive breathing assistance
• Stage 5: Death

The early motor neurone disease symptoms may vary from person to person, depending upon the type of ALS and the age of the person. In general, as motor neurons are damaged, a person will gradually start to complain about difficulties in voluntary movements. Based on which part of the body is affected, and motor neurone disease types, a set of symptoms can be noted:

Limb Onset: More than 70% of the individuals have reported initial symptomatic appearance in the arms or legs.

Accordingly, symptoms in the upper limb onset include:

• Sudden numbness in hands and fingers
• Stiffness in arms or fingers
•  Cramps
• Occasional events of dropping objects
• Lack of dexterity and fumbling

Symptoms associated with lower limb onset include:

• Difficulty walking
• Occasional tripping or stumbling
• Difficulty in lifting the front half of the foot
• Bulbar ALS is a form of ALS, where motor neurons are affected in the brain stem area, particularly in the corticobulbar region.

Its typical symptoms include:

•  Slurred speech
• Difficulty in swallowing
• Muscle spasm in throat and face
• Certain rare types of ALS such as respiratory onset ALS are characterized by breathing difficulties that aggravate over the period.  

Symptoms associated with upper and lower motor neurons include

• Involuntary rhythmic muscle contractions
• Muscle spasticity
• Overactive reflexes
• Spontaneous twitching
• Muscular weakness

Researchers are figuring out the exact cause of ALS by understanding various genetic and molecular pathways. However, genetic mutations, increased oxidative stress, dysfunctions at the cellular levels, as well as neuroinflammation are identified as the possible mechanisms triggering the onset of ALS. The environmental risk variables pinpointed so far are sports with high incidences of concussions, military jobs, and lifestyle obligations leading to continuous exposure to heavy metals, lead toxicity, pesticides, neurotoxins as well as electromagnetic fields.

Some studies have proposed a link with the regional factors causing ALS; which was demonstrated with the statistical data that the rate of occurrence of ALS in the Western Pacific region, West Papua New Guinea, and Japan’s Kii Peninsula is 140 cases higher per hundred thousand people.

• What is the life expectancy of a person with Motor Neuron Disease?
• Life expectancy depends upon several factors like age, family history, other co-morbidities, age of diagnosis, etc. On a general note, epidemiological studies have reported life expectancy of people suffering from Motor Neuron Disease is between 3 to 4 years, post-onset of ALS/MND. However, with the advent of alternative treatment possibilities, it is now possible to extend the survival limit with symptomatic relief in pain management, better bowel and bladder control, better control over mood swings, irritability, etc.
• What are the 3 stages of MND?
• ALS/MND is broadly classified based on symptomatic severity, which should be noted as early stage, middle stage, and later stage of MND. In the early stage of the disease, a person can only experience muscle weakness, shortness of breath, slurry speech, clumsiness, etc. During the middle stage of symptomatic ALD/MND, a person will report difficulty in moving, joint pain, uncontrollable yawning, breathing difficulty, etc. While in the advanced stage a person needs supportive assistance in all important day-to-day tasks.
• What is the treatment procedure?
• As a regulatory obligation, each individual has to be informed about the details of the procedure before enrolment; and the same is documented with the help of informed consent. Once the person shows interest in alternative treatment for ALS/MND, he is counseled by our neuro specialists on the panel to understand his medical history, current health status, and his future expectations from the treatment. Once a patient gets to agree to undergo treatment with this novel approach, he or has to undergo certain pre-procedural tests to assess his/her inclusion criteria for the treatment. Once he gets qualified he will be ready for the alternative treatment protocol for MND. We have mastered the technology, wherein we use customized cellular communication language to promote the production of new cells and reduce the aging of mature brain cells. A person is also advised of various supportive rehabilitation programs as mentioned herewith.
• What is the success rate of the treatment?
• Our years of research and science as well as medical expertise have supported us to offer advanced technology that has reported good improvements in clinical studies. The statistical analysis conducted has shown a 70-80% improvement in the life expectancy of the patient, while 80-90% of the people have reported reduced severity of the symptomatic exhibition, post-treatment.