Understanding and Treatment of Rare Metabolic Disorders

Generoso Andria and a group of five other partners from around Europe have been working together to improve the understanding and treatment of Lysosomal Storage Diseases (LSDs). LSDs are a relatively rare group of metabolic disorders caused by genetic defects that affect the synthesis or processing of lysosomal hydrolases, the enzymes that are responsible for the hydrolytic breakdown of macromolecules within cells..

The European Consortium for Lysosomal Diseases (EUCLYD) has been focusing on four specific LSDs – Gaucher disease, Pompe disease, Mucopolysaccharidosis VI and Multiple Sulfatase Deficiency – each with their own unique characteristics. “We got involved in research on LSDs because it is a very promising field in the area of ‘inborn errors of metabolism’ (a blanket term referring to all congenital metabolic disorders).”

“Some novel and very encouraging therapeutic approaches have been developed in the last few years, and we were interested in supporting and contributing to the development of these approaches”.

Collaboration

Andria describes how through contacting colleagues from around Europe, a network of consultation between the main centres involved in research and clinical care for LSDs was formed, the likes of which could not have been realised at national level. This is due to national funding agencies tending to be reluctant to grant funds to the study of rare diseases.

Once EUCLYD had been formed, a set of collective goals were created. “The project has focused on three different aspects in which to investigate in this group of diseases: the pathophysiology and mechanisms causing the symptoms, the natural history of the diseases and the testing of novel therapeutic approaches.”

Pathophysiology

The pathophysiology of LSDs is already understood in broad terms, but the minutiae of the processes involved in each disease are lacking.

There is a wide variability between the genetic, molecular, pathological and clinical features of different LSDs, and even between each patient with a given disease, but there is an order of pathogenic events common to most of them. A genetic defect in the coding for an aspect of lysosomal function (usually for a specific lysosomal enzyme) causes lysosomal dysfunction, meaning that the lysosomes are unable to break down certain substances that then accumulate within the cells. This results in disruption to the function and structure of organs, with often devastating consequences. Secondary effects also occur, and data suggests that mechanisms including apoptosis, systematic inflammation and autophagy can be involved.

“The role of autophagy has been extensively investigated in multiple sulfatase deficiency and Pompe disease cells,” Andria says.

Andrea Ballabio and his co-workers, of the Telethon Institute of Genetics and Medicine, have discovered that lysosome-mediated degradative pathways are regulated by a specific gene network, named CLEAR (Coordinated Lysosomal Expression and Regulation). The CLEAR network is comprised of several classes of genes, including genes that belong to the lysosomal complement (hydrolases, transporters, accessory proteins) and genes that participate in lysosomal biogenesis and function. They found that most lysosomal genes share one or more copies of a GTCACGTGAC regulatory motif in their promoters, which is the target site of the bHLH transcription factor EB (TFEB). TFEB overexpression increases the number of lysosomes in the cell and improves cellular degradative capabilities. This suggests that there are possible therapeutic applications of the CLEAR-mediated lysosomal enhancement not only in lysosomal storage disorders, but also in neurodegenerative diseases such as Alzheimer’s.

Andria stresses the importance of this line of research. “All this goes to show that understanding the mechanisms of the diseases and what is happening within the cells is crucial in developing new strategies for the treatment of patients.”

New treatments

“We have investigated a number of different therapeutic strategies for these diseases, including enzyme replacement therapy, substrate reduction therapy, gene therapy and more recently enzyme enhancement by the use of pharmacological chaperones.”

“The late-onset Pompe disease patients, treated at various stages of disease severity by enzyme replacement therapy, were evaluated by both the Dutch and the German groups in multicenter studies and demonstrated stabilization of neuromuscular deficits, with mild functional improvement.”

Pharmacological chaperones, or pharmacoperones, are small molecules that are designed to bind to specific target proteins, such as enzymes, and help to stabilize them. “Giancarlo Parenti’s group in Naples have begun to study possible treatments of Pompe disease with pharmacological chaperones. They have shown that these molecules can be potentially effective in 10-15% of patients with Pompe disease carrying specific mutations. They have also demonstrated a synergistic effect of chaperone therapy and enzyme replacement therapy. This effect is not limited to Pompe disease, and may be seen in any LSD for which both a chaperone and enzyme replacement therapy are available.”

“These results may well suggest an impending paradigm shift in terms of using the two techniques together. We are now at the stage where we have approved a clinical trial in Italy to investigate the combined administration of recombinant enzymes and a chaperone in Pompe disease patients.”

“Studies of treatment are also being carried out using animal models,” Andria continues. “In the field of gene therapy Auricchio’s group recently demonstrated long-term amelioration of feline Mucopolysaccharidosis VI after AAV-mediated liver gene transfer, that may represent a promising therapeutic strategy for MPS VI patients.”

“One of our partners, Professor Stefan Karlsson of the University of Lund, Sweden, has developed a non neuronopathic mouse model for Gaucher Disease that will be used for preclinical studies on both gene therapy and substrate reduction therapy with new molecules”

Karlsson, along with Professor Timothy Cox of Cambridge (who pioneered the use of enzyme replacement therapy in Gaucher disease) and other members of EUCLYD will be hoping that their research can pave the way for the future of new treatments in LSDs, as well as other metabolic diseases. Impending clinical testing of new treatments means that it is only a matter of time before this research reaches the patients’ bedsides.

Click here to access the project website.

Published: Friday, 30th September 2011