Stem Cell Treatment for Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy is a hereditary neurological disorder characterized by loss of motor neurons innervating different muscles of the body. Despite being a rare disorder, affecting around one infant out of at least 10,000 live births, it is still one of the leading hereditary causes of infant disability and death. This disorder has a wide range of subtypes and symptom severity. The most common SMA, which is known as type 1 SMA, accounts for more than half of the cases and it is a severe form of SMA that follows an autosomal recessive inheritance. Spinal muscle atrophy mainly occurs due to a genetic abnormality in the SMN gene coding for proteins responsible for normal nerve functioning. This protein abnormality affects motor neurons – i.e. nerves supplying muscles versus sensory nerves – therefore causing characteristics of SMA (1-3).

As previously mentioned, SMA has a wide range of symptom severity, and not all symptoms might be present at the same time or with the same severity. Common SMA symptoms include (2):

Muscle weakness: According to the SMA subtype, this weakness can range from as little as mild weakness diagnosed during adulthood (type 4) up to severe debilitating generalized muscle weakness impairing neonatal development (type 1). Infants with severe SMA typically present with:

• Difficulty swallowing and suckling while breastfeeding
• Difficulty holding up their heads
• Difficulty sitting up
• Difficulty reaching normal developmental milestones

In some milder/intermediate forms of SMA, infants might be able to sit normally, but might not be able to walk

• Muscle Atrophy: Muscle atrophy is defined as wasting of muscles or reduced muscle mass due to the long-term lack of innervation and movement. This process of atrophy increases with age the longer the period of absent innervation and movement.
• Reduced muscle tone (Hypotonia)
• Respiratory problems: This is seen in severe SMA subtypes due to respiratory muscle weakness. Infants with severe SMA could develop aspiration, collapsed lungs, and could have recurrent respiratory infections as a result. Some children might have respiratory failure as a result of this respiratory weakness.
• Reduced lifespan: For people affected with the more severe types, especially type 1, the lifespan of these patients is unfortunately compromised.

Despite there being lots of advancements aiming at knowing the exact genetic mechanism responsible for SMA earlier in order to allow prompt management and to provide a better quality of life for children and adults living with such a debilitating condition, there has not been much progress in treating its original cause – i.e. abnormal nerve proteins. Current treatments only aim to alleviate or prevent possible complications from this muscle weakness such as (1, 3): Pulmonary/Respiratory support: These supportive measures include educating parents about the course of the disease and its possible complications, and anticipating/predicting respiratory symptoms early on to prevent their progression. Such measures include routine immunization against common respiratory infections and learning how to properly assist children while coughing to prevent them from acquiring aspiration or infections. Mechanical ventilation might be needed in people with severe symptoms and frequent infections. Nutritional support: This involves giving children with swallowing and/or feeding difficulties semi-solid diets to compensate for their lack of adequate chewing and gastrointestinal problems. Some children with severe nutritional difficulty might require gastrostomy placement (an external opening into the stomach for direct stomach feeding). Movement support: This involves multidisciplinary treatments aiming to improve the quality of life of people with SMA and allow them to reach their full potential and maintain some level of independence. Some examples include using walking/movement aids such as wheelchairs and standing frames. Physiotherapy and aquatic therapy and swimming training might also be used to improve muscle endurance. In some patients with associated positional deformities (ex. scoliosis or sideward bending of the spine), they might benefit from orthopedic surgical correction of the deformity to allow better posture and range of movement. Gene therapy: This is a novel form of therapy which involves intravenous or oral administration of the “genetically-modified” functional form of the SMN gene – which is the originally defective gene in SMA. However, this treatment is still novel and quite expensive; with some commercially-available drugs requiring maintenance yearly –or even more frequent – injections for life-time to maintain the obtained benefits. This creates a major financial burden for most individuals till this time since not all countries cover its use within insurance policies; and even if sometimes it is covered by insurance, it is usually associated with strict inclusion guidelines restricting its use in many infants with SMA. Another problem seen with this treatment is that not all SMA patients are eligible to receive it and that it might be associated with some side effects including elevated liver enzymes and bone marrow suppression in many of the treated individuals – which might be a problem when used in such young patients (4, 5). As you can see, all of these treatments are solely supportive or rehabilitative in nature, and even the newly-produced forms of gene therapy still have a long way before becoming more readily available for the public and before having better data regarding their long-term efficacy as well as its side effect profile.

To date, there has not been a single study – to our knowledge – that has compared different types of stem cells, concerning safety and efficacy, particularly in patients with SMA.

There are currently many types of stem cells available to use in different conditions including embryonic stem cells, mesenchymal stem cells (ex. bone marrow and umbilical cord stem cells), hematopoietic stem cells, neural stem cells, as well as many other sources (6).

However, when looking at other similar neurodevelopmental disorders and at different stem cell therapy trials, the most feasible-to-obtain and safely-used stem cells that have been used and tested in people with other neurological conditions are the mesenchymal stem cells such as those obtained from either umbilical cord-derived samples, both cord blood and cord tissue, or bone marrow stem cells. These two types provide the best results in neurological conditions since they easily cross the blood-brain barrier, to reach the brain and the spinal cord, and have the lowest possible side effects (7).

Studies are also currently testing the use of genetically-modified stem cells that can be acquired from SMA patients to allow for self-reinjection of stem cells that have been modified to harbor normal SMN protein. These cells are known as induced pluripotent stem cells (iPSCs). The aim of this technique is to prevent possible side effects or allergic reactions due to the transplantation of “foreign” cells from donors other than the patients themselves. However, this technique is still not clinically applicable in the medical field (8).

Therefore, our work is currently still based on one of the only clinical studies testing stem cell therapy in SMA patients which found that mesenchymal stem cell therapy provided visible benefits when administered using two concomitant routes of administration; both intravenous and intrathecal routes; versus when they used solitary intrathecal route (10).

These results have contributed to establishing our current method of dual-type stem cell administration.

One problem seen with SMA is that its window of opportunity is quite short, especially in infants with type 1 SMA. This period is not exactly known; however, at some point, even if we intervene using stem cell therapy, clinical benefit might not be optimum – or might be temporary to the duration of stem cell therapy injections. This has been suggested by one study that noted that the benefits seen in their type 1 SMA patients – who were all older than 7 months old – had temporary benefits despite them showing significant improvement during the period of therapy. They have therefore advised that earlier stem cell therapy might be a solution; prior to permanent damage to the neurons of children with SMA. Of course, this treatment window differs according to the SMA subtype your child has and the severity of their symptoms, and the reason most trials done on patients with SMA showed partial benefits is possible that they recruited older infants with the more severe type 1 SMA type who had probably acquired permanent neuron damage due to their older age (9, 10). Therefore, for people with type 1 SMA an age prior to 4 to 6 months might be the optimum window for treatment. People with less severe forms might however have benefits long after this period depending on the severity of the symptoms. This is why we recommend consulting our specialists prior to treatment in order to estimate the degree of benefit that can be obtained from stem cell therapy. We can generally say that the earlier stem cell therapy is initiated, the better the expected results are.

Of course, no treatment is without complications, and stem cell therapy is the same. However, despite its novelty, stem cell therapy has limited side effects if used properly, with comparable general side effects to those experienced with regular blood transfusion or foreign organ transplantation (ex. allergic reactions, cell rejection, or fever). Additionally, in studies specifically studying stem cell therapy in SMA, no actual side effects were reported given the already-severe presentation of these infants prior to starting stem cell therapy. However, when using stem cell therapy in similar conditions, none of these previously mentioned side effects reported were life-threatening or had life-long consequences, and they were easily managed medically at the time of their occurrence (11).

We have summarized the different factors that might affect your response to stem cell therapy, and how we at Beike Technology address each factor to ensure that we provide you with the highest efficacy using the safest procedure possible.

• Dose/Number of stem cells: The higher the dose of stem cells – within limits of course – the better the response. At Beike Technology, we administer an optimum dose of around 120-400 Million Cells (depending on the child’s weight and age) for SMA.
• Route/Method of administration: Studies have shown that combining intrathecal injection (through lumbar puncture directly within the brain’s CSF) with the traditional intravenous route provides a better response than administering intravenous injections alone (which causes stem cells to go to other organs than the brain before reaching the brain). Therefore, at Beike Technology, we use both intravenous and intrathecal routes concomitantly in order to obtain maximal efficacy; while ensuring the least possible side effects or toxicity.
• Type of Stem Cells used: Both umbilical cord-based stem cells, which we use at Beike Technology, and bone marrow stem cells have better-proven efficacy in SMA compared to other types of stem cells.
•  Timing of stem cell transplantation: Early intervention is crucial for people with SMA. Therefore, we recommend early intervention soon after diagnosis depending on the type of SMA your child has.
• Follow-up Time: Significant benefits from stem cell therapy in patients with SMA begin appearing around 4 weeks after stem cell therapy, and most people reach their full potential around 3 months after treatment. At Beike Technology, even after discharge, we provide you with a full follow-up program beginning as early as one month and up to one year after transplantation. You have complete access to our professional team even after you leave our center.