Two approaches to treat Lysosomal Storage Diseases

April 15, 2014
Two approaches to treat Lysosomal Storage Diseases

Enzyme therapy proves effective in treating LSDs, whilst gene therapy is an upcoming contender.

Lysosomes are membrane-bound organelles found in most animal cells. They are responsible for treating cellular waste. Genetic mutations in lysosomal enzymes lead to lysosome malfunction and waste accumulation. And this leads to a whole range of complex metabolic disorders, collectively called Lysosomal Storage Diseases (LSD). There are two kinds of LDSs: those that affect the brain (neuropathic) and those that do not (non-neuropathic). The EU-funded EUCLYD project, completed in 2011, studied four non-neuropathic LSDs out of the 50 currently known. These were Gaucher disease, Pompe disease, the mucopolysaccharidosis (MPS) VI and the multiple sulfatase deficiency.

Enzyme replacement therapy was one of the approaches successfully implemented by the project. "As the name suggests, it consists of artificially synthesising the malfunctioning and administering it to patients through an injection every seven to fifteen days," says project coordinator Generoso Andria, director of the Paediatrics Department of the University of Naples, Italy. The newly synthesised enzyme is then able to reach the lysosome directly and perform its functions. The project also studied a gene therapeutic approach. "We can operate 'upstream' with respect to the ," Andria tells "We prepared a viral vector that could insert the normal gene directly in the affected chromosome," he explains, adding: "In December 2012 we started testing this gene therapy to make sure it is not toxic. And we plan to recruit patients soon."

Importantly, the project also changed how the lysosome is viewed. "We used to think that the lysosome functioned as the 'incinerator' of the cell," explains Andria. "It is quite an appropriate metaphor, at least here in Naples, with all the waste problem we have had," he adds jokingly. Yet the reality is a bit more complicated than that, as Andria tells "Just as with the waste in a city, we realised that rather than 'incinerating', for the lysosome, it is more efficient to 'recycle' different molecules, like sugars, after degrading them."

One expert believes that enzyme therapy is a simple solution. "Most of the LSDs are due to mutations that inactivate a single protein that encodes an enzyme in a metabolic pathway in the lysosme," explains Peter Lobel, an independent expert who is professor at theDepartment of Biochemistry and Molecular Biology of the Robert Wood Johnson Medical School, New Jersey, USA. "Therefore, in principle it is very simple to correct this. When you are missing a particular enzyme, if you replace it, you restore the function. The biggest problem is for the enzyme to be taken up by the cells that need it. But other than that, this is an effective way to fix the disease," he tells

Another expert agrees that this is the best approach for now. "Provided you can reach the right target organs, the therapy works really well," explains Thomas Kirkegaard Jensen, chief scientific officer at Orphazyme, a biotech company based in Copenhagen, Denmark, that also focuses on these diseases. "The problem is that organs like kidney, heart, and cartilage are much harder to get to than the liver or the spleen. Not to mention the brain, of course, protected by the impenetrable blood brain barrier," he tells

Diseases affecting the brain were explicitly excluded from the project because of the hurdles posed by the . "Today it is nearly impossible to reach the brain, unless you inject it directly with a viral vector," says Kirkegaard. "It is a very big organ, 2,000 times bigger than a mouse brain where we have performed the tests. You need multiple infusions and, most importantly, we need to control and balance the production levels of the missing enzyme. Even too much of it might be harmful," he says. He adds: "I am confident, though, that this is the way to go,"

On the other hand, gene therapy has received a number of setbacks in the past due to the death of some patients treated with this method. The sector is, however, improving. "In the last ten years, though, science has improved significantly in this sector," Kirkegaard notes. "We are currently lacking the economic incentive for industries to invest in this field. It is very expensive to guarantee safety and efficacy. But once we secure a viable payment model, this is the future," he tells

Both Kirkegaard and Lobel mention a paper in Science in 2013 that showed very promising results treating a neurodegenerative lysosomal storage disease, called MLD, with gene therapy. However, "while it is an advance over , current gene therapy is not perfect," warns Lobel. "In the enzyme replacement therapy, the 'good' gene is expressed by a limited number of cells, practically turning them into factories." But with gene therapy, "if the new DNA in the cell persists, you do not have to cure patients once a week with a recombinant enzyme," he tells "There might be unanticipated effects with the viral vectors we use. But today we can control them better and avoid vectors that cause the cells to proliferate and produce cancer. We won't know for sure if will show long term efficacy or adverse effects, but for the medium term, it looks very promising," says Lobel.

Explore further: New therapy against rare gene defects

Related Stories

New therapy against rare gene defects

April 15, 2014
On 15th April is the 1st International Pompe Disease Day, a campaign to raise awareness of this rare but severe gene defect. Pompe Disease is only one of more than 40 metabolic disorders that mainly affect children under ...

Gene therapy for lysosomal storage disease shown to be safe and well tolerated

March 11, 2014
Several young children suffering from a severe degenerative genetic disease received injections of therapeutic genes packaged within a noninfectious viral delivery vector. Safety, tolerability, and efficacy results from this ...

Mouse study shows gene therapy may be possible cure for Hurler syndrome

February 4, 2014
Researchers used blood platelets and bone marrow cells to deliver potentially curative gene therapy to mouse models of the human genetic disorder Hurler syndrome – an often fatal condition that causes organ damage and other ...

Gene therapy cures a severe paediatric neurodegenerative disease in animal models

July 2, 2013
A single session of a gene therapy developed by the Universitat Autonoma de Barcelona (UAB) cures Sanfilippo Syndrome A in animal models. This syndrome is a neurodegenerative disease that affects between 1 and 9 out of every ...

Experimental molecular therapy crosses blood-brain barrier to treat neurological disease

February 4, 2013
Researchers have overcome a major challenge to treating brain diseases by engineering an experimental molecular therapy that crosses the blood-brain barrier to reverse neurological lysosomal storage disease in mice.

Gene therapy bolsters enzyme activity to combat Alzheimer's disease in mice

December 3, 2013
St. Jude Children's Research Hospital scientists have identified an enzyme that can halt or possibly even reverse the build-up of toxic protein fragments known as plaques in the brains of mice with Alzheimer's disease. The ...

Recommended for you

Google searches can be used to track dengue in underdeveloped countries

July 20, 2017
An analytical tool that combines Google search data with government-provided clinical data can quickly and accurately track dengue fever in less-developed countries, according to new research published in PLOS Computational ...

MRSA emerged years before methicillin was even discovered

July 19, 2017
Methicillin resistant Staphylococcus aureus (MRSA) emerged long before the introduction of the antibiotic methicillin into clinical practice, according to a study published in the open access journal Genome Biology. It was ...

New test distinguishes Zika from similar viral infections

July 18, 2017
A new test is the best-to-date in differentiating Zika virus infections from infections caused by similar viruses. The antibody-based assay, developed by researchers at UC Berkeley and Humabs BioMed, a private biotechnology ...

'Superbugs' study reveals complex picture of E. coli bloodstream infections

July 18, 2017
The first large-scale genetic study of Escherichia coli (E. coli) cultured from patients with bloodstream infections in England showed that drug resistant 'superbugs' are not always out-competing other strains. Research by ...

Ebola virus can persist in monkeys that survived disease, even after symptoms disappear

July 17, 2017
Ebola virus infection can be detected in rhesus monkeys that survive the disease and no longer show symptoms, according to research published by Army scientists in today's online edition of the journal Nature Microbiology. ...

Mountain gorillas have herpes virus similar to that found in humans

July 13, 2017
Scientists from the University of California, Davis, have detected a herpes virus in wild mountain gorillas that is very similar to the Epstein-Barr virus in humans, according to a study published today in the journal Scientific ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.