Motor Neuron Diseases: The Promise of Regenerative Medicine

Motor neuron diseases are a group of disorders affecting the nervous system with specific involvement of motor neurons. These diseases are progressive in nature and result in poor balance, coordination, and posture. Their management is complex owing to their clinical variation. Moreover, they spread to the non-motor regions and manifest as a multisystem disorder leading to sensory and cognitive impairment. The low survival period has urged the development of an effective treatment modality. Stem cells hold the key to regeneration, rendering them as suitable therapeutic candidates.

Understanding the Disease

Motor neurons govern the movement of muscles, thus controlling activities like walking, breathing, swallowing, etc. These neurons, or nerve cells relay signals between the brain, spinal cord, and muscles. The brain conveys signals to the spinal cord via upper motor neurons, and spinal cord transmits them to the muscles via lower motor neurons. The clinical heterogeneity has divided these diseases into diverse categories. One category is based on the involvement of upper or lower motor neurons, dividing motor neuron diseases into the following four types.

Amyotrophic Lateral Sclerosis: It affects both upper and lower motor neurons.

Progressive Bulbar Palsy: It includes upper motor neurons without any effects on limbs.

Progressive Muscular Atrophy: It involves lower motor neurons adversely impacting the limbs.

Primary Lateral Sclerosis: It impacts the upper motor neurons and exhibits slow progression.

Similarly, they are also called familial and sporadic, with the causative factor being either family history or unknown, respectively.

Due to the involvement of motor neurons, muscles are the most affected tissue. They weaken and atrophy as the disease progresses, attributing to the lack of nerve excitation to muscles.

Exploring the Cellular Pathways

Amyotrophic Lateral Sclerosis (ALS) has been the most prevalent among all motor neuron diseases. It is also well-known as Lou Gehrig’s disease after the ballplayer who suffered from ALS. Approximately 25 genetic mutations have also been identified in ALS patients by last year. However, the signaling pathways in cells responsible for ALS are still not elucidated. It has been suggested that defects in pathways including RNA metabolism, DNA repair, protein homeostasis, free oxygen radical formation, intracellular transport, etc., cause ALS. Moreover, dysregulated immune response exerted by the cells surrounding nerve cells also impacts negatively. The overstimulation of nerve cell receptors, particularly by glutamate ligand, also causes nerve cell damage. Mitochondrial mutation and reduced functioning has also been implicated. The situation worsens with decreased levels of factors that support nerve growth. Therefore, the collective impact of these pathways results in nerve cell death, and the connection between nerve cells is lost.

The Limits of Conventional Treatment

Currently there is no cure for ALS. Merely three medications- riluzole, edaravone, and sodium phenylbutyrate are available. Among them, only riluzole improves survival by reducing the overstimulation of nerve cells, which also slows the disease progression. Edarevadone, a free radical scavenger and sodium phenylbutyrate only reduce the rate of the disease trajectory. Additionally, rehabilitation therapies like speech therapy, occupational therapy, physical therapy, psychotherapy, and nutrition support aid in symptom management. However, none of the modalities can reduce the damage and restore the motor functions.

Mesenchymal Stem Cells: The Hope for ALS

Mesenchymal stem cells (MSCs), with their ability to differentiate into nerve cells, can provide the desired therapy for ALS. They can also regulate the immune system and diminish the levels of free oxygen radicals. Moreover, MSCs switch cell-damaging M1 macrophages to cell-repairing M2 macrophages. They also secrete trophic factors that stimulate the regeneration process in the local tissue environment. These factors also include VEGF, BDNF, and TGF-1 that protect the nerve cells. The conventional therapy focuses on one cellular pathway, a lacuna that MSCs quickly overcome by their impact on multiple pathways. MSCs prevent more nerve cell loss and also promote nerve cell growth, thus restoring the link between nerve cells and the motor functions. The convenient in vitro expansion of MSCs also adds to its numerous benefits.

Clinical Trials: Translating Regenerative Medicine

Mazzini et al. conducted the first clinical trial with MSC transplantation in ALS patients in 2003 and proved that they do not exhibit adverse effects. The same group in 2012 performed another trial with a 9-year follow-up and demonstrated increased life expectancy with no negative impact. Another trial exhibited an increase in immune cells (regulatory T cells and helper T cells) that prevent immune system-based harm to nerve cells. The trials also showed increased respiratory capacity and improved functional ability in ALS patients. Several clinical trials have established the potential of MSC therapy in ALS.

Conclusion

Motor neuron diseases are progressive neurological disorders, exhibiting drastically low survival periods. ALS is the predominant motor neuron disease with survival up to 3-5 years. In the absence of efficient medications, regenerative medicine has provided an alternate therapy. MSCs, with their multifaceted approach, can considerably improve the nerve damage in ALS patients. Clinical trials have shown their effectiveness without exerting any side effects. MSCs can be non-invasively isolated from the umbilical cord with the added advantages of cost-effectiveness, abundant cell number, and higher differentiation potential. Advancells is the pioneering stem cell manufacturing company in India. It offers high-quality MSCs isolated from umbilical cord by a team of expert scientists.