Are stem cell therapies a treatment alternative for ALS

Amyotrophic lateral sclerosis (ALS) is a rare disease which causes the degradation of motor neurons. Its cause(s) and the underlying mechanism is not yet identified and up to date no therapy exists to cure or halt the progression of ALS, ultimately causing fatal respiratory failure. Besides few medication options to prolong the life expectancy by several month, only few alternative, exploratory therapies exist, including treatments with stem cells or stem cell conditioned media. The following chapters summarise current knowledge on ALS, standard and alternative therapies, stem cells and its secretome and how they are used as therapeutic regimen in clinical trials.

ALS is a rare motor neuron disease whose onset usually starts between the age of 40 and 70 but in some cases can start already in the twenties. It is characterised by progressive muscular weakness caused by the degeneration of motor neurons, initially leading to muscle weakness/stiffness but ultimately causing fatal respiratory failure after approximately 3-5 years ^iv (Rowland & Shneider, 2001). To date there is no cure for ALS and no treatment available which can completely halt or even reverse the progression of the disease. The reason for the onset of ALS is sporadic (90-95%), which means that there is no common cause and everybody, no matter which age, sex or ethnic background can in principle develop ALS. Nevertheless, some genetic modifications have been identified which increase the chance of developing ALS and can cause familial ALS (5-10%) ⁱⁱⁱ (Muzio, Viotti, & Martino, 2021).

As there is no option to cure ALS, no standard therapy exists which is used by all physicians worldwide. The treatment is rather a personalised supportive health care with individualised treatment plans which covers different aspects of the disease ^vi (Sykova, Cizkova, & Kubinova, 2021):

1. Medication
2. Nutritional Support – Prepare small meals with appropriate calorie intake
   • Riluzol. It decreases glutamate levels in motor neurons and is believed to reduce overall damage. Survival is prolonged by ~ 2-3 month ⁱ(Corcia, Beltran, Bakkouche, & Couratier, 2021).
   • Edaravone. An anti-oxidant that has been reported to slow the progression of ALS.
   • Different treatment of symptoms caused by ALS (against cramps, stiffness, excess saliva etc.)
3. Physical Therapy – Training doesn’t stop the degradation but can train (yet) unaffected muscles which can prolong the independence of the patient.
4. Breathing and Communication Support – With ongoing muscular degradation the ability to breathe and talk will be affected. Ventilation support and computer-based speech support can be applied.

The main problem with the current treatment options is that they only treat ALS symptoms and do not effectively halt or even reverse the ongoing muscular degradation. It is therefore essential to develop therapies that are able to stop the degradation or at least prolong the survival significantly, which is usually only 3-5 years after diagnosis.

No alternative treatment to cure or stop ALS-progression does exist but scientists are working on three promising alternative approaches which might be used in the future as potential therapies, if they succeedⁱ (Corcia et al., 2021).

1. It is essential to understand the reasons for the specific death of motor neurons which seems to be caused by a variety of cellular defects (protein recycling, gene regulation, structural impairments). Additionally, cells of the immune system seem to be involved (glial cells).
   
   If the underlying mechanism is understood, a more specific drug-treatment can be developed.
2. Several genes have already been identified which are risk-factors for the development of ALS. Gene-therapy approaches are being tested to modify the activity of certain genes of interest via epigenetic modification.
3. Stem cell research is a third approach, and one that has attracted considerable scientific interest. It is being investigated for ALS and related neurodegenerative diseases such as Alzheimer's, and may open new therapeutic avenues if the research succeeds.

Stem cells are well-known for their potential to differentiate and grow during our whole life, constantly replenishing various cell types. Those cells are mainly localized in our bone marrow but also in some other niches within our body. Since scientist revealed the potential of these immortal cells, they have been within focus for the development of certain technologies. There are two basic ideas behind using stem cells to treat ALS ^vi (Sykova et al., 2021):

1. The substitution of the damaged tissue by injection of stem cells to the affected area. Many different clinical studies have already been filed to investigate the best route of administration (intracerebral, intrathecal, intravenous, intravascular) of certain stem cell types (e.g. mesenchymal or hematopoietic stem cells) and how often they need to be injected.
2. As a supportive role to provide neuroprotection due to direct cell-cell interaction or secreted proteins and microsomes.

Early results indicate that such transplantation has not cured ALS, though some studies have reported longer survival times in treated patients. These are early findings that still require confirmation in larger trials. Five clinical studies* are currently ongoing that use stem cells to treat ALS alongside other treatment regimens.

Stem cell isolation, their cultivation and in vitro expansion are quite complex procedures, especially if they are meant to be reinjected in vivo. On the one hand, the risk of contamination and subsequent rejection of the cells might occur. On the other hand, cells that are expanded too rapidly might loose their potency or might transform into cancer cells if treated with complex cocktails of growth factors for too long. Hence, the whole process must be strictly controlled throughout the whole life cycle of the cells, from isolation to reinjection or the therapy might cause adverse effects or be simply ineffective.

One reason for the beneficial effects observed after injection of stem cells in research might be the secreted compounds (cytokines or other biologically active proteins) into their so-called “microenvironment”. The entirety of these secreted compounds, which are incorporated within exosomes, is called “secretome”.

Several publications report that this secretome contains growth factors that may protect neurons and glial cells and may support anti-inflammatory and anti-apoptotic processes in the surrounding tissue ^ii,v (Marconi et al., 2012; Shin et al., 2021). It is also discussed whether exosomes transfer miRNA, which play a key role in inter-cellular communication (Shin et al., 2021). Scientific data support the theory that injection of stem cell conditioned media can mitigate the severity of the injury and enhance functional recovery of spinal cord injury in animal models ^v(Shin et al., 2021). In animal models of ALS, both stem cells and their secretome have shown beneficial effects, and the secretome alone appeared sufficient, suggesting that injecting the cells themselves may not be necessary.

The secretome provided by ANOVA IRM is an autologous MSC secretome preparation. Only one donation is necessary to isolate your own mesenchymal stem cells, which are then cultivated in vitro for a short period to generate sufficient stem cell-conditioned medium containing the exosomes secreted by your cells. After the cells are separated from the medium, your personalized secretome undergoes internal quality control before it is used for up to 10 applications, scheduled according to your individual needs. Manufacturing takes place in Germany under the applicable pharmaceutical regulations and the supervision of the competent German authorities.

The secretome approach differs from the injection of stem cells in several practical respects. Because the cells are cultivated over a short period under mild conditions, the risk of losing potency during cultivation is low. As no living cells are administered, the risks specifically associated with injecting expanded cells — such as cell-related infection or malignant transformation of the injected cells — do not arise with this cell-free approach. Your personalized secretome-containing medium is generated and stored until it is needed, so an appointment does not have to be rescheduled if the cells do not grow as expected, which can occur when stem cells themselves are to be injected. Manufacturing is carried out in Germany under the applicable pharmaceutical regulations and supervision.

Whether Stem Cell Secretome may be an option in your case depends on your current health status and your individual medical situation. If you would like to know more, you can schedule an appointment. Our doctors will review your medical files and discuss with you whether this approach could be considered for you. Stem-cell-based and secretome therapies remain developing medical approaches; the available evidence varies by indication, individual outcomes cannot be predicted, and treatment is offered only following an individual medical assessment.