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Gene therapy cures childhood brain disease in animal models

01 Oct, 2013

Researchers at Universitat Autònoma de Barcelona (UAB) in Spain have announced the success of a gene therapy trial in curing a neurodegenerative disease, Sanfilippo syndrome A, in animal models.

According to their published research, a single session of a gene therapy cured Sanfilippo syndrome A in mice and larger animal models using beagle dogs.

Sanfilippo syndrome

The incidence of Sanfilippo syndrome A, Mucopolysaccharidosis type IIIA (MPSIIIA), the most common form of Sanfilippo syndrome, varies geographically, with approximately 1 case per 100 000 live births. The disease is caused by a mutation of the gene that encodes the enzyme sulfamidase, leading to deficiencies in the production of the enzyme, which is essential for the breakdown of substances known as glycosaminoglicans.

According to the researchers, if glycosaminoglicans are not broken down, they accumulate in the cells and cause neuroinflammation and organ dysfunction mainly in the brain but also in other parts of the body. Children born with this mutation are diagnosed from the age of 4–5 years. They suffer neurodegeneration, causing mental retardation, aggressiveness, hyperactivity, sleep alterations, loss of speech and motor co-ordination, and at present, they die in adolescence.

The disease is generally inherited as autosomal recessive – that is, both the mother and the father are unaffected carriers of the disease, but each pass a recessive gene onto a child.

Injecting AAV9 vectors

The treatment the research team used consisted of a single surgical intervention using a serotype 9 adeno-associated viral vector encoding sulfamidase, which was injected into the cerebrospinal fluid – the liquid that surrounds the brain and the spinal cord. The harmless virus genetically modifies the cells of the brain and the spinal cord so that they produce sulfamidase and then spreads to other parts of the body like the liver, where it continues to induce production of the enzyme.

Animals’ behaviour and life expectancy normal

Once the enzyme’s activity was restored, glycosaminoglican levels returned to normal for life in the animal models, their accumulation in cells disappeared, along with the neuroinflammation and dysfunctions of the brain and other affected organs, and the animal’s behaviour and its life expectancy returned to normal. For example, mice with the disease lived only up to 14 months, whereas those given the treatment survived as long as healthy ones.

In their published paper, the researchers write that, in the animal models, brain function (correction of behavioural deficit) did appear to be restored when the therapy was delivered early enough – a result not previously reported given that, for most lysosomal storage diseases (LSDs), clinical signs appear once some degree of tissue damage has already occurred.

Translatable to large animal model

“In summary, intra-CSF [cerebrospinal fluid] delivery of AAV9 [serotype 9 adeno-associated viral vector] vectors led to transgenic expression in widespread areas of the CNS [central nervous system], PNS [peripheral nervous system] and liver, with reversal of central and somatic pathology in MPS IIIA mice leading to full correction of behavioural deficits and substantially extended lifespan. These results are fully translatable to a large animal model, showing long-term expression of the species-specific transgene and similar transgene biodistribution to mice when vector was delivered using a procedure commonly used in paediatric neurosurgery. Our results provide strong evidence supporting the clinical translation of this approach to treat MPS IIIA and other LSDs affecting the CNS.”

The results of the research were published in the July 2013 issue of the Journal of Clinical Investigation.

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