ALPHA-MAN

Clinical development of Enzyme Replacement Therapy in alpha-Mannosidosis patients using recombinant human enzyme

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 Obiettivo del progetto (Objective)

'Alpha-Mannosidosis is a rare Lysosomal Storage Disorder with a worldwide incidence of about 1:500 000. This orphan and devastating disease is caused by the deficiency of the lysosomal alpha-mannosidase (LAMAN) which is responsible for the intralysosomal degradation of mannosyl linked oligosaccharides. To date no causative treatment for alpha-Mannosidosis is available and since most of the children are born healthy, an early initiated therapy could contribute to a normal development. To develop an efficient therapy for this disease the collaborative research project EURAMAN and HUE-MAN were initiated within FP5 and FP6, respectively. Within these collaborative networks, European scientists, clinicians and the industry successfully i) developed an efficient pre-clinical Enzyme Replacement Therapy (ERT) protocol using recombinant human (rh) LAMAN in a mouse model for alpha-Mannosidosis, ii) built up a database collecting patient data and iii) defined clinical endpoints for the future clinical trials in alpha-Mannosidosis patients by an European wide natural history study. Furthermore, the HUE-MAN network developed the conditions for a large-scale production of the recombinant enzyme and the way is now paved for the first clinical trials in man, which we aim to realize within FP7. The main objectives of the ALPHA-MAN project are i) the performance of efficient clinical trials (phase I-III) in alpha-Mannosidosis patients, ii) a better understanding of the pathophysiology and the mechanism of how the recombinant enzyme enters the cells of the central nervous system by performing ERT in a newly generated immuntolerant alpha-Mannosidosis mouse model, which allows chronic treatment and iii) the determination of the minimal effective dose with chronic treatment in the immuntolerant mice.'

Introduzione (Teaser)

Existing treatments for the orphan disorder alpha-mannosidosis are mainly supportive and symptomatic. A European study plans to change that by developing a novel enzyme replacement therapy (ERT).

Descrizione progetto (Article)

Alpha-mannosidosis is a rare disease associated with an impaired breakdown of polysaccharides. It is caused by mutations in the gene encoding the lysosomal enzyme alpha-mannosidase (LAMAN), and leads to mental retardation and death in early childhood.

Currently, ERT constitutes the most promising treatment for most lysosomal storage disorders. It entails introduction of the recombinant enzyme into the patient's circulation, which gets picked up by the cells and rescues the lysosome deficiency. However, no ERT has been developed for alpha-mannosidosis.

The scope of the EU-funded http://www.alpha-man.eu/ (ALPHA-MAN) project was to develop a therapeutic strategy using recombinant human enzyme for patients suffering from alpha-mannosidosis. The project based its work on the activities of the predecessor HUE-MAN project regarding large-scale production of the recombinant human enzyme and development of an ERT protocol.

Considerable effort was devoted to finding the optimal drug dose for correcting the central nervous system pathology in mice. A new disease mouse model was developed that recapitulated the human alpha-mannosidosis phenotype. Treatment of mice resulted in an overall improvement of brain-associated symptoms. Researchers also made interesting pre-clinical observations regarding the long-term outcome of ERT based on discovery of the receptors that carry the rhLAMAN across the blood-brain barrier.

The HUE-MAN project performed clinical trials in alpha-mannosidosis patients in centres across Europe, using the medicinal enzyme product rhLAMAN as a therapeutic agent. Enzyme administration was well-tolerated in patients and showed a statistically significant improvement for a number of the biochemical and clinical efficacy end points.

Additionally, the http://amamutdb.no (disease mutation database) has been further developed to include new data from 27 additional patients. In total, the mutation database now contains genetic, biochemical and clinical data on more than 240 patients. Collectively, this information provides a comprehensive picture of the genetic aetiology of alpha-mannosidosis.

The success of the ALPHA-MAN project to establish rhLAMAN as an ERT approach to the treatment of alpha-mannosidosis was communicated through press releases and conference presentations. It constitutes the first specific and evidence-based therapeutic intervention for this untreatable disease.