Different routes of administration of an enzyme against diseases (…)

A comparison of different routes of administration of a recombinant enzyme for the prevention of neurodegenerative disorders in lysosomal storage disease

Nine lysosomal diseases now benefit patients from specific treatments based on defective enzyme supply. These diseases are Gaucher (type 1 and 3), Fabry, Pompeii, MPS I (Hurler / Hurler-Scheie and Scheie), MPS II (Hunter), MPS VI (Maroteaux-Lamy), MPS IV disease (Morocco type A) and Olman disease and cholesterol ester overload since late 2015. This contribution is made by weekly infusions depending on the disease or every 15 days. We are talking about enzyme therapy. On the same principle, other diseases are currently the subject of clinical trials.

Limitations of enzyme therapy

If these treatments improve the quality of life of patients and slowly, stabilize, even correct some of their symptoms, and sometimes make it possible to change them in a very significant way, then unfortunately they are not very effective or very effective in neurological diseases. In fact, the brain has a natural barrier, the blood-brain barrier, which protects it from potential pathogenic agents (examples: bacteria, viruses) that lend itself to the blood system. Thus, intravenously administered enzymes do not overcome this natural barrier and therefore cannot correct the overload present in brain cells.

Therapeutic ways to prevent neurodegenerative disorders

For several years, researchers have been trying to suppress this defense by conducting studies of lysosomal enzyme injection into cerebrospinal fluid (CSF) of animal models for lysosomal disease. Cerebrospinal (or cerebrospinal, CSF) fluid bathes the brain and spinal cord. Its role is to protect the brain from injury and to transport substances. Three areas of administration of enzymes in CSF are possible: at the level of the brain to the ventricle or cerebral cistern (ventricles are deeper and the sisters are more superficial), or at a lumbar level away from the brain. (Intrathecal injection). In studies conducted on animal models (11 different lysosomal diseases), researchers have so far supported intracerebral injection (ventricle and / or cistern) and have been able to demonstrate a reduction and improvement in the overload of neurological disorders.

Although studies of mouse models of MPS II have shown that the administration of enzymes by intrathecal route has made it possible to detect it in the brain, the long-term effects on the brain remain unknown. However, intrathecal administration, which is less complex, is currently used in clinical trials of children with MPS I, MPS II, and MPS IIIA.

So a research team decided to compare different routes of enzyme administration in this disease, in MPS IIIA dogs. These administrations were made in young puppies when the symptoms of the disease have not yet been revealed. However, from birth, puppies have an overload of heparin sulfate in their brain cells, which increases over time.

The first results and ways of research

The results of their work show that intrathecal administration makes it possible to find enzymes in brain cells both surface (cortex) and depth (thalamus). The authors also noted a decrease in heparin sulfate overload and induced neuroinflammation in this disease. However, overload reduction is less important for deep regions of the brain and neuroinflammation is not reduced.

In an effort to improve these results, the authors suggested increasing the duration of treatment (in the present case, the treatment lasts 8 weeks at the rate of one injection per week), or increasing the amount of enzymes administered. The results obtained by administration at the level of cistern of the brain are similar to those of intrathecal. Administration of the enzyme at the ventricle level makes it possible to achieve better results for deep regions but this method is much more invasive.

Delphine Genevaz, Scientific Manager VML

Publications: Therapeutic protein supply for the prevention of neurodegenerative changes: Comparison of different CSF-delivery methods. N. R. Marshall et al. Experimental Neurology. September 2014

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