Introduction 

Central Core Disease (CCD) is a genetically inherited disease that affects the muscles and how they function. Under the microscope, it can be seen that the muscle fibres have ‘cores’, indicative of areas where the muscle does not work properly. These areas have a reduced number of mitochondria and less oxidative activity than normal, which is critical for muscle function.¹ 

The severity of CCD varies across patients. In some cases, the muscles have severe weakness during infancy, whereas others can develop symptoms later on in life.² The diagnosis of CCD includes taking a muscle biopsy, assessing clinical symptoms, and conducting magnetic resonance imaging. The histopathological analysis from muscle biopsy shows central cores in muscle fibres, and their characteristics may show differences across patients of different ages and disease severity.¹ 

Currently, the management of CCD involves the use of a multidisciplinary approach to treat the symptoms of the disease, such as physiotherapy.¹ There are currently no approved therapies for CCD that address the cause of the disease; this is a considerable problem due to the large level of need. Presently, emerging therapies, primarily gene therapy and pharmacological therapies, are being investigated as disease-modifying treatments.³ This article will explain CCD and give a concise overview of the emerging therapies that could provide relief for CCD patients. 

Understanding central core disease

What is CCD?

CCD is a congenital myopathy, which is characterised as a muscle disease that is inherited and present from birth. The issues can be with the muscle or nerve cells that control the muscle.⁴ This means that CCD is a ‘neuromuscular disease’. Individuals affected by the disease have difficulty in controlling the muscles and carrying out simple motor activities, even those such as eating and breathing, along with physical defects caused by problems during development.¹ 

CCD is present from infancy, when it is marked by lower muscle tone, especially around the hips and shoulders. Infants may also struggle with achieving their developmental milestones. Additional symptoms include scoliosis, foot irregularities, and risk of malignant hyperthermia.¹ Malignant hyperthermia is characterised as an unusual reaction to drugs that are known to relax the muscles, such as anaesthetics. This is a very serious condition and can be fatal in some cases.¹

Genetic causes and underlying mechanisms 

CCD is caused by mutations in the gene encoding the skeletal muscle ryanodine receptor (RYR1). The RyR1 protein is a receptor located in the sarcoplasmic reticulum of muscle cells, where it functions as a channel for the flow of calcium ions (Ca++) from inside the sarcoplasmic reticulum to the cytoplasm.⁵ This movement of calcium ions is stimulated by the excitation from neurons, and is necessary to initiate the contraction of muscle fibres, required for their function. 

Many forms of mutations of RYR1 were reported in individuals with CCD, including missense and deletion mutations. Most of these mutations are dominant, meaning that inheriting one copy of this mutated gene is sufficient for the disease to develop.⁵ These mutations lead to changes in the shape of the RyR1 protein. In particular, these changes to the protein make this calcium channel ‘leaky’, leading to calcium ions getting out of the channel when they shouldn’t. This then affects the regulation of calcium levels within muscle cells, disrupting neuronal excitation and contraction of muscle cells.⁵

Current symptomatic management

The treatments for CCD involve a combination of different therapies; however, currently, none are able to cure the disease. The current management options include physiotherapy that is aimed at keeping the muscles working well and preventing their tightness. Recommended exercises include swimming and horse riding.¹ Notably, high endurance training should be avoided.

 It is also important to check lung function regularly and treat chest infections promptly, as breathing problems can be seen in CCD patients. The use of ventilators can also be recommended in severe cases.¹ Due to the risk of CCD patients having malignant hyperthermia, non-triggering anaesthetic drugs should be used, and it should be assumed that the CCD patient has malignant hyperthermia unless it is proven otherwise.¹

Emerging and investigational therapies 

Gene therapy 

Gene therapy includes the administration of DNA or RNA molecules to patients, either once or a few times, until the effect is shown. This type of therapy targets a more upstream mechanism than those targeted by pharmacological therapy. In other words, it aims to fix the mutated gene or its protein product, meaning that a wider range of the underlying disease mechanisms can be targeted.³ 

Gene therapy can be applied at the mRNA level, aiming to silence the mRNA product that is made from the mutated RYR1 gene. Different strategies can be used. For example, short interfering RNAs (siRNAs) can be designed to match the patient’s mutation on the RYR1 gene to silence this faulty copy of the gene. Even though this could be effective, it only works in the muscles into which the siRNA can be injected, and specific siRNAs must be designed for different RYR1 mutations present in different patients. Antisense oligonucleotides (AONs) can also be used; they prevent the inclusion of the problematic exon into the mRNA product. Even though this has been shown to be beneficial in some clinical trials, this strategy can cause problems with different parts of the protein. Even though these approaches are promising, there are limitations with their delivery.⁶ 

Apart from gene therapy targeting RNA, it can also be applied at the DNA level, aiming to fix or replace the faulty copy of the RYR1 gene. There are two main ways of achieving this. Firstly, gene replacement can be used, where a good copy of the RYR1 gene, producing the normal and functioning protein, can be delivered to the muscle cells using a viral vector. This gene therapy is more beneficial to individuals with recessive CCD. In this case, CCD patients who suffer due to a recessive mutation may benefit more than those who have a dominant mutation, because, as for the patients with dominant CCD, the mutant protein would still interfere in the process.

Unfortunately, this means that gene replacement has limited success for those with the dominant RYR1 mutation. It is estimated that around 43% or more of the pathogenic RYR1 variants can be targeted in this way. Another form of gene editing is via CRISPR. This technique uses engineered virus-like particles to cut segments of the RYR1 gene and aims to repair the mutation.⁶ 

Pharmacological therapy 

The emerging pharmacological therapies fall into two main groups: drugs that lower oxidative stress while also protecting the RyR1 channel, and drugs that act directly on the RyR1 protein to modulate its activity.³

Rycal S48168

Rycal S48168 is a small molecule modulator that preferentially binds the faulty RyR1 channel protein and helps the protein to adopt its closed conformation and aiming to stop the leak from this calcium channel without interfering with normal muscle contraction. It was demonstrated that the administration of Rycal at 120-200 mg doses for 29 days was well tolerated and had no serious side effects, with benefits including less fatigue and improved muscle strength.⁷ 

N-acetylcysteine 

The faulty RyR1 channel can lead to an increase in oxidative stress in muscle cells. N-acetylcysteine (NAC) is a promising orally taken antioxidant, which could be effective in lowering oxidative stress and improving muscle function. However, so far,  it has not been proven effective for CCD patients. ⁸ 

Salbutamol 

Salbutamol, also known under the same albuterol, is an example of a β2-agonist. This drug is helpful in increasing the strength of muscles. Research shows that it improved the condition of children aged three and six months, when 8mg per day was administered for six months,  including walking, respiratory function, and muscle function. It was also reported to be safe and generally well tolerated by the patients.⁹

Conclusion

In conclusion, both gene and pharmacological therapies have their own strengths and limitations. For instance, pharmacological therapy, such as orally taken drugs, is useful because they are easy to administer, and it is easier to intervene in case of side effects. However, they may not be as effective due to targeting only a few of the many underlying disease mechanisms. 

Gene therapy, on the other hand, has the potential to main the underlying causes of the disease; however, it may also have much more serious and difficult-to-reverse side effects and a greater biological risk. 

Overall, these therapies have long-term potential and high efficacy if they work well; however, there are currently issues with their delivery and safety. Also, it is important to characterise different gene therapies for different RYR1 mutations, meaning that personalised treatments are required.⁶  

Summary

Central Core Disease (CCD) is a condition affecting muscle function and physiology. It is caused by genetic mutations in the RYR1 gene that encodes a calcium channel protein in muscle cells, which has a key function in regulating muscle contraction in response to neuronal stimulation. A large unmet need towards disease-modifying therapies for CCD drives the high volumes of research in this area, where gene and pharmacological therapies are investigated. Currently, there are no approved disease-modifying therapies, but there are clinical trials that show success, indicating the potential of this field.