Are stem cell therapies a treatment alternative for MS?

Multiple sclerosis (MS) is a chronic inflammatory, autoimmune and neurodegenerative disease of the central nervous system. 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 MS. Therapies focus mainly on treating MS symptoms and by suppressing the immune system to slow down further damage, causing severe side effects. Only few alternative, exploratory therapies exist, including treatments with stem cells to substitute autoreactive T- and B- cells and reduce inflammation. The following chapters summarise current knowledge on MS, standard and alternative therapies, stem cells and their secretome containing exosomes and how they are used as therapeutic regimen in clinical trials.

While Amyotrophic lateral sclerosis (ALS) causes progressive muscular weakness caused by the degeneration of motor neurons, Multiple Sclerosis (MS) is focussed on nerves from the brain and spinal cord, the so called central nervous system. As with most autoimmune diseases the causes for the onset are still unknown, although the cause for the neuronal degradation is well-characterised. A protective fat layer called myelin sheath surrounds all nerve fibres, comparable to the isolation of an electrical cable, to prevent the loss of the electrical current which is transmitted from the brain to other regions of the body and back^I. Unfortunately, this layer is attacked by the own immune system, causing inflammation in the central nervous system and ultimately the destruction of this sheath. This damage is visible in brain MRIs as so-called plaques. In consequence, messages like e.g. “lift the arm” will not reach their target, causing certain disabilities to move. While the causes are still unknown, some risk factors to develop MS have been identified so far, which includes factors that you can avoid and some that you cannot ^I:

• Age, sex, race and family history seem to be risk factors. MS occurs the most in white women at the age between 20-40.
• Viral infections with e.g. Epstein-Barr is linked to development of MS and other autoimmune diseases e.g. Type 1 diabetes can also increase the risk to develop MS.
• Low exposure to sunlight (low Vitamin D levels) and smoking seems to be important too.

While MS symptoms can largely differ between patients, three different types of MS can be differentiated based on disease progression. While primary-progressive MS (10-15% of the MS patients, PP-MS) is constantly getting worse over time, relapsing-remitting MS comes and goes in waves, causing sudden MS attacks and disease progression (RR-MS) followed by partial or total recovery. In later stages, sometimes triggered by interferon therapy, RR-MS can switch to secondary progressive multiple sclerosis (SP-MS) with slow but continuous worsening of symptoms.

Unfortunately, as with ALS, no curative therapy is available for MS and therefore no standard therapy exists which is used by all physicians worldwide. Initially, it might be necessary to diagnose MS and its grade of severeness with specific methods like blood tests to detect specific biomarkers, lumbar puncture to identify unusual antibodies and MRI, to identify inflammatory patches, plaques or lesions in the brain. Depending on the grade and type of the disease the following treatments can be applied ^I,II:

1. Treatments for MS attacks might be needed in urgent cases

   The most common treatment for MS attacks are corticosteroids such as prednisone and methylprednisolone to reduce nerve inflammation, causing sometimes severe side effects like insomnia, mood swings and increased blood pressure. If corticosteroids are not effective, a plasmapheresis can be applied which basically exchanges the plasma of your blood to get rid of the inflammation-promoting parts (cytokines, chemokines) within your blood.

2. Treatments to slow MS progression

   Primary-progressive MS can only be treated by one officially approved disease-modifiying therapy, namely Ocrelizumab, a monoclonal antibody which slows down the progression to a certain extent by eliminating B cells, which contribute to the disease severity ^II.

   Available treatment regimens for relapsing-remitting MS are more diverse but they have in common that they modulate the activity of the immune system. The most commonly prescribed intravenous treatment is Interferon beta medication, which uses natural body mechanisms to suppress T cell activity. Depending on your symptom and disease progression it can be followed by oral medication with e.g. Fingolimod which “traps” T cells within their lymph nodes, thereby reducing autoimmune damage but at the same time reducing the ability of your body to respond to real infections. Many other compounds can be used like Teriflunomide, Cladribine or antibodies like Natalizumab, Alemtuzumab or the already mentioned Ocrelizumab which have in common that they cause severe side effects (e.g. hypertension, leukemia, viral infections) ^II.

3. Treatment of MS signs and symptoms

   The onset of MS causes numbness or weakness in one or more limbs, tremor, lack of coordination and can even cause vision problems including blurry / double vision or partial / complete loss of vision. Physical therapy can help to strengthen your muscles and the use of muscle relaxants may help to reduce painful spasms. Additional medication might be appropriately applied in case of fatigue, depression, insomnia or sexual dysfunction.

   Cannabinoids are used to limit tremor, muscle stiffness and spasms, neuropathic pain as well as sleep and bladder disturbanceand are used more often now, as evidence is increasing on effectiveness. ^VI

The main problem with the current treatment options is that they only treat MS symptoms and do not effectively halt or even reverse the degradation of the central nervous system. In a 60-year long study to compare the life expectancy of 1388 MS patients, it was concluded that MS patients have in average a 7-year shorter life expectancy compared with healthy people ^III. It is therefore essential to develop therapies that are able to stop the degradation, increase the patients’ quality of life by reducing severe side-effects or at least prolong the survival significantly.

No alternative treatment to cure or stop MS-progression does exist and no scientific evidence is available to support the application of certain diets, the use of Marijuana or other treatments based on natural medicine; which does of course not exclude that it might help to reduce pain or other symptoms. As the damage is being dealt from your own immune system and the cause for the onset of the autoimmune response is not yet discovered, there is no scientific option to cure the disease in the short run. Nevertheless, promising alternative treatments to reduce pain and inflammation and regenerate tissue are investigated by using stem cells, which are able to modify the body´s immune reaction naturally with hopefully no negative side-effects and have the potential to stimulate tissue regeneration.

Stem cells are well-known for their potential to differentiate and grow during our whole life, constantly replenishing various cell types. Newer results additionally show, that stem cells have a large potential to modulate the immune system. Stem cells are localized in our bone marrow as well as our abdominal belly fat 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 several ideas behind using stem cells to treat MS ^I:

1. The use of hematopoietic stem cells as approach to stop MS progression.

   After isolation of hematopoietic stem cells they can be sorted with FACS to accumulate cells that express a certain surface marker (CD34) which is absent on autoreactive cells. These cells are expanded in vitro and reinjected into the patient after the ablative destruction of the immune system with chemotherapeutics. The autologous stem cells are supposed to engraft and regenerate the immune system, hopefully without developing autoimmune cells again. This approach is still under clinical investigation (NCT00273364, NCT03133403) but the outcome is promising. Nevertheless, the procedure is very dangerous and there is no guarantee that it works.

2. The use of mesenchymal stem cells (MSC) as approach to decrease inflammation and nerve damage.

   It is a well-accepted fact that MSC mediate anti-inflammatory reactions. Initial clinical studies with MSCs as treatment for MS indeed reduced inflammation and pain but some came with negative effects like infections, toxicity and malignancy development when in-vitro cultivated MSCs were injected as clinics were not sufficiently legally controlled. Different handling mechanisms are still under investigation e.g. the source of MSCs such as bone-marrow-derived mesenchymal stem cellsBM-MSC (NCT01815632, NCT01228266) or adipose -derived MSC (adMSC) which are more often used as fat is easily accessible (NCT01056471, NCT02326935).
   This approach to date seems to be the safest and most elegant stem cell approach for MS. Treatment with MSCs is aimed to naturally repress the auto-immune reactions thereby halting inflammation and at the same time allow for and stimulate regeneration by internal stem cells present in the brain and spinal cord. However, it is important to check whether the clinic has a legal permission to ensure the quality of the stem cells (sterility, toxicity, malignancy). The secretome which does not contain cells is a huge step towards eliminating one risk: malignancy or cancer transmission.

3. The use of neural stem cells (NSC) as approach to substitute nerve damage.

   This approach is in its beginning and still focusses on pre-clinical animal experiments. In theory neural stem cells can be generated out of MSC, injected at the site of tissue damage and support regeneration. However, this approach is the least elegant or smart as the brain itself contains stem cells, it is impossible to inject such cells to all sites of damage in the brain and it is improbable that differentiated cells will move to the site of damage as long as inflammation is present. Such approaches have led to the worst scandals in stem cell therapy so far.

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. Patients should always ask for legal permits if they consider treatment as this ensures quality and safety.

One reason for the observed beneficial effects after injection of stem cells might be the secreted compounds (exosomes, cytokines or other biologically active proteins) into their so-called “microenvironment”. The entirety of these secreted compounds, which are partially incorporated within exosomes and partially are suspended in the liquid phase, is called “secretome”. Scientists and clinicians may use the complete secretome but in most cases use only the isolated exosomes which lack the soluble factors.

Several publications already showed that this secretome contains neuroprotective growth factors which can protect neurons and glial cells and at the same time activate anti-inflammatory and anti-apoptotic pathways within the surrounding tissue ^{IV, V}. It is also discussed if exosomes transfer miRNA which play a key role in inter-cellular communication ^V. Scientific data supports 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. Results from animal models for ALS showed that the use of stem cells or its secretome does have beneficial effects but it appears as if the secretome alone is sufficient, indicating that it is probably not necessary to inject the stem cells.

The secretome provided by ANOVA IRM contains exosomes and soluble secreted factors and is fully legally controlled. It does not contain cells that carry the risk of malignancy. ANOVA IRM is the first institution world-wide to acquire legal permission by the regulatory bodies. Only one donation is necessary to isolate your own personal, so-calles autologous, mesenchymal stem cells from belly fat which are then cultivated in vitro for a short period to generate sufficient amounts of minimally-manipulated stem cell-conditioned medium which contains the exosomes and soluble factors secreted by your stem cells. After separating the stem cells from the medium, your own personalized secretome will undergo a thorough pharmaceutical quality control before it is being used for up to 10 treatments, which will be scheduled according to your special needs. All internal processes are controlled by German Drug Authorities and are therefore highly regulated to yield the best quality and highest safety available.

There are many advantages when using the ANOVA secretome over the injection of stem cells. As the stem cells are cultivated over a short period of time and under mild conditions there is only a low risk of loss of potency during the cultivation. No cells have to be reinjected and therefore the risk for infections or the risk to develop cancer from the pluripotent stem cells does not exist. Your own personalized secretome-containing medium will be generated and stored until you need it. The freezing does not largely change the composition. In contrast, classical MSC treatments are 1 time therapies which does not seem reasonable, as stem cells are not a cure and therefore, on-going treatment is needed. If stem cells are frozen, their behavior seems to change rendering them potentially less effective which does not allow for freezing for repeated therapy. Finally, you can rely on the highly regulated system of the German Drug Authorities when it comes to quality and safety of the final product.

Whether Stem Cell Secretome is a treatment option for you depends on your current health status and the underlying problem in your specific case. If you would like to know more about your treatment options with Stem Cell Secretome, schedule an appointment today. Our scientists and doctors will assess your medical files to see if you can benefit from stem cell treatment.