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Promising treatment for rare neurological disorder

New research suggests that a combination treatment of gene therapy and bone marrow transplants could prove to be a promising treatment for infants with Batten disease, a rare but fatal neurological disorder. Scientists from the Institute of Psychiatry (IoP) at King’s College London and Washington University School of Medicine in St Louis (USA) discovered dramatic improvements in life span and motor function in mice with the infantile form of the disease treated with this combination therapy. 

Batten disease is the common name for a group of inherited genetic diseases called the Neuronal Ceroid Lipofuscinoses (NCLs), which affect about 1 in every 30,000 births and there are approximately 200 affected children and young adults in the UK. Infants with Batten disease appear healthy at birth but soon become blind, speechless and paralysed, and will die at a young age. There are no effective treatments for the disease, and several previous therapeutic approaches evaluated in mouse models and in young children have until now produced disappointing results.

Professor Jonathan Cooper from the IoP at King’s, and co-author of the new study published in Annals of Neurology, says: ‘Our findings were surprising because the combination therapy we tested proved to be far more effective than either of the two treatments alone. Indeed, the bone marrow therapy alone had no positive effect, but when we combined it with gene therapy to the brain it had a dramatic effect. Although the combination therapy did not cure the disease, it more than doubled the lifespan of the mice and significantly delayed the decline in their motor skills.’

The study tested various therapies in four groups of newborn mice with infantile Batten disease: (i) gene therapy only; (ii) bone marrow transplants only; (iii) combined gene therapy and bone marrow transplants; and (iv) no treatment. As a comparison, the study included healthy mice without the disorder.

Bone marrow transplants alone had no effect on lifespan compared to untreated mice with Batten disease - animals in both groups lived approximately 8.9 months (the normal lifespan of a mouse is 24 months). Batten disease mice that got only gene therapy lived 13.5 months, while those that got the combination therapy lived for 18.5 months. The researchers noted similar synergistic effects of the therapies when they evaluated motor function. Untreated mice and those that received only a bone marrow transplant experienced significant decline in motor skills by 6 months, but for those that got combination therapy, motor skills did not begin to decline until 13 months and did so more gradually than in the other mice.

Professor Mark Sands from Washington University and senior author of the study says: ‘Until now, this disease has been refractory to every therapy that has been thrown at it. The results are the most hopeful to date, and they open up a new avenue of research to find effective therapies to fight this devastating disease.’

There are several forms of the disease, diagnosed at different ages, and all are related to the inability of cells to break down and recycle proteins. The infantile form is caused by mutations in the PPT1 gene that codes for an enzyme needed to remove these proteins from cells. Without a working copy of the gene, the proteins build up in cells, causing seizures, brain atrophy and dementia. The disease progresses most rapidly when it is diagnosed in infants. By age 2, most live in an unresponsive, vegetative state.

Gene therapy to replace the PPT1 enzyme was delivered directly into the brain and the authors suggest that the normal immune cells from the bone marrow transplant help reduce inflammation in the brain which helps the PPT1 enzyme process the proteins properly in the cells.  Mice that got the combination therapy also had higher levels of active PPT1 enzyme in the brain, a thicker cerebral cortex and fewer accumulated proteins in brain cells, all indicators that the treatment is working.

The researchers are now repeating the experiment and investigating other ways to reduce inflammation in the brain that would not involve the risks of a bone marrow transplant. One possibility involves anti-inflammatory drugs that have effects in the brain.

Professor Sands adds: ‘We may be able to achieve the same results with a less invasive anti-inflammatory treatment. We’re very excited now to move forward.’

The research was supported by the National Institutes of Health (NIH), Ruth L. Kirschstein NRSA Fellowship, The Wellcome Trust, Batten Disease Family Association, the Batten Disease Support and Research Association and the Bletsoe Family.

For full paper: Macauley S.L. et al. ‘Synergisitc effects of CNS-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis’ Annals of Neurology (Feb. 24, 2012) doi: 10.1002/ana.23545

The findings will be further discussed at the 13th International Conference on Neuronal Ceroid Lipofuscinoses 28-31 March 2012, which is co-organised by Professor Cooper. For more information, please visit the conference website.

For more information, please contact Seil Collins (Press Officer) by email: or tel: 0207 848 5377