The mucopolysaccharidoses: from gargoylism to gene therapy

An image to illustrate mucopolysaccharidoses, gargoylism and gene therapy

Professor Susanne Gerit Kircher looks at past therapy options for mucopolysaccharidoses and explores what the future might hold.

Mucopolysaccharidoses are a group of rare inherited lysosomal storage diseases, which were first described a hundred years ago by Charles Hunter (1917) and Meinhard Pfaundler and Gertrud Hurler (1919). None of these medical scientists used the word ‘mucopolysaccharidoses’, however, as this term – and the basic chemical substances involved, mucopolysaccharides – were not identified until 1952 in the brain and 1957 in the urine of affected patients by Albert Dorfman and Andrew E Lorincz.

Gargoylism

Gargoylism describes patients with dysmorphic facial features, a large head, upturned nose, enlarged tongue, and thickened gingiva. All these signs were observed early on in patients with the classical forms of mucopolysaccharide storage disease (MPS). The missing knowledge about the nature of these rare disorders was the reason that the name ‘gargoylism’ was used as there was a perceived similarity with gargoyles, the carved stone grotesques used in architecture during the Hellenistic and even more in the Gothic period, whose function was to spout water from roofs and walls of a building, thereby preventing rainwater from running down the walls and causing erosion. The Austrian paediatrician Meinhard Pfaundler and his colleague Otto Ullrich also discussed the term in connection with the noise of gurgling water which sounds similar to a patient’s noisy breathing with, typically, an open mouth.

For decades, these diseases described by the Scottish physician Hunter and the paediatricians Pfaundler (Austria) and Hurler (Germany) were called ‘gargoylism’, symbolising the strange nature of the faces and the ‘gestalt’”. This description was even used until the 1980s, when the different disease types were characterised by numbers (MPS I – IX) or the name of the scientist who first described the subtypes: Hurler, Hunter, Sanfilippo, Morquio, Maroteaux, Lamy, and Sly. The subtypes MPS I (Hurler), II (Hunter) and VI (Maroteaux-Lamy) were most often synonymously described as gargoylisms. But, in fact, for a long time, many syndromic patients with coarse facial features were diagnosed as ‘gargoyles’.

Mucopolysaccharides – complex sugars molecules

The nature of the stored sugars – the so-called mucopolysaccharides (MPS) – in cells, tissue, and organs which are excreted via the urine of affected patients, were identified in a group of similar patients. Histologic staining of tissue with Alcian Blue or the urinary excretion measured by Toluidin and Alcian Blue made it easier to narrow down the particular patients group. Some of these rare patients showed an increasing storage which caused hepatomegaly, splenomegaly, macroglossia, thickened skin and macrocephaly. Others were characterised by severe skeletal deformities and dwarf-like stature. A third group did not really show the specific facial signs, but a severe mental retardation. The nature of the MPS enabled pathologists to identify these stored materials as acid glycosaminoglycans, substances found in the extracellular matrix of connective tissue, cartilage, and bone tissue. Therefore, MPS disorders were recognised as diseases of the connective tissue.

First therapies based on the little knowledge of these rare diseases

Hunter described the clinical symptoms in two brothers with inguinal and umbilical hernias. Therefore, the first known therapy was in the form of a hernia truss shown in pictures in his publication from 1917. The small stature, enlarged head, macroglossia and intellectual impairment brought Pfaundler and Hurler to think about hypothyroidism, and the first therapy they used consisted of iodide substitution, which was not helpful. Understanding the nature of MPS as a connective tissue disorder then enabled them to develop the idea of substitutng patients with corticosteroids in order to heal ‘rheumatism’. Vitamin C (ascorbic acid) should favour the cross-linking of collagen fibrils.

Subsequently, supportive therapy improved with hearing aids, corneal transplantations, operations for the decompression and stabilisation of the craniocervical junction to prevent tetraplegia and sleep apnea. The frequently-observed hearing impairment due to chronic otitis media was treated by adenoidectomy and ventilations tubes. Hydrocephaly and increased intracranial pressure were corrected by shunt-operations. Cardiomyopathy and thickened heart valves were treated by cardiologists, and carpal-tunnel-syndrome by surgeons. The main interest was that patients could survive longer. But it was soon clear that a real life-extension was not possible.

Enzyme-deficiencies are causing storage

It was in 1968 when Joseph C Fratantoni, Clara W Hall and Elizabeth F Neufeld published the faulty degradation of mucopolysaccharide as the defect in Hurler´s and Hunter´s syndromes. Due to mutations in the responsible genes for enzyme production, patients had severe deficiencies of the MPS-degrading enzymes. This was a milestone in the therapeutic options as it seemed to be logical to substitute the missing enzymes. Enzymes were extracted from the urine of horses and bovines, as well as from human placental material, but they seemed to be unstable and not sufficiently effective. As such, patients were treated by providing them with a blood infusion and plasma/serum/isolated leukocytes. An effect was notable but not long-lasting. Furthermore, enzymes found in brewer’s yeast or diets with methionine-reduced ingredients did not seem to be effective.

In 1981, the first bone marrow-transplant for an MPS patient was performed, with the aim to implant donor cells with sufficient lysosomal enzymes, including the special enzyme missing in that patient. It was thought that circulating leukocytes and mesenchymal stem cells should be able to invade different tissues and to supply the cells with the missing enzymes. This theoretical approach was indeed correct and is still valid today, with the restriction that this method must be performed very early on, often at an age when the patients are not yet diagnosed.

In the first years of this century, the first enzyme-replacement therapy in MPS I was successful in clinical trials and subsequently approved. Followed by the developed enzyme-replacement-therapies for MPS VI, MPS II, MPS IVA, MPS VII, one can say with some certainty that a new era in the therapy for affected MPS patients has begun. With moderate and manageable side-effects, thousands of MPS patients are now being treated in that way.

The limitations of enzyme-replacement-therapies

15 years after first treatment of MPS patients there is now time to identify successes and failures. The main disadvantages were identified as the inability to penetrate the blood-brain-barrier, which is eminent in all neurological problems, especially in the neuronopathic MPS types. The second problem, which is not yet solved, is the modest influence on the skeleton, in that any restricted growth and changes of the most involved meta- and epiphyses cannot be really improved. Furthermore, other tissues with low vascularisation, such as the eyes or cartilage tissue, cannot benefit from the bolus-like higher concentrations during the enzyme infusion and the otherwise low concentrations between the weekly treatments.

Therefore, other ways of enzyme supplementation have been developed. Similar to the active transport of other larger molecules and protein-particles, natural receptors in the brain tissue were used to incorporate fused proteins, the natural protein, like transferrin or hormones, fused with the missing enzyme protein. Another promising strategy is to conjugate the therapeutic enzyme with polymer-based nanoparticles, which are able to pass the blood-brain-barrier by transcytosis. Promising in-vitro studies suggest that these strategies will be part of the future therapy in MPS.

Gene therapy

Gene therapy was already a focus of clinical studies for MPS before enzyme replacement therapy became available for many patients. However, the comparatively lower risks of haematopoietic stem cell therapy or enzyme replacement therapy have somehow pushed gene therapy into the background, but technical progress has also improved any possibilities for beneficial gene manipulation.

Gene therapy aims for the correction of genetic sequences in patients’ cells. There are two possibilities to influence the patient’s organism: with the ex vivo approach, one removes, for example, a patient’s stem cells or fibroblasts and genetically changes the patient’s DNA and injects such corrected autologous cells consecutively back into the patient. In contrast, the in vivo gene therapy approach tries to correct the mutated patient’s DNA by replacing mutated genes with genes which have the correct DNA-sequence and which express the correct gene product (the enzymes necessary for MPS-degradation).

In order to target different tissues and organs with these correct genes, viral vectors (lentivirus, adenovirus) act as transport vehicle and penetrate the DNA or RNA of host cells. Lentiviral vectors can also be used to augment the efficacy of haematopoietic stem cells, inducing over-expression of the required enzyme. This is not a dream for future – it is already, in fact, being used in animal trials and the clinical trials for MPS patients, especially in patients with neurological involvement, such as severe forms of MPS II and MPS III. By injection directly into the brain or ventricles, the results show stabilisation or improvement of cognitive function and adaptive behaviour. It is expected that gene therapy will be the third pillar of the therapy of the future, longside symptomatic therapy and enzyme supplementation therapies.

Ass Prof Dr Dr Susanne Gerit Kircher
Austrian MPS Society
+43 14016038077
susanne.kircher@meduniwien.ac.at

www.mps-austria.org/

 

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