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The ALPHA MAN Project

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

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Project summary

The lysosomal storage disorder (LSD) alpha-Mannosidosis is a rare genetic disease affecting less than 500 people worldwide and according to the EU regulations, designated as an "orphan" disease. Alpha-Mannosidosis is caused by an enyzme defect due to mutations in the gene for lysosomal acid alpha-Mannosidase (LAMAN) affecting the lysosomal and cellular glycoprotein catabolism with severe consequences for the organism. In humans, LAMAN deficiency results in progressive mental retardation, skeletal changes, hearing loss and recurrent infections and many patients die during early childhood. Today, the most promising therapy for lysosomal storage disorders including alpha-Mannosidosis is Enzyme Replacement Therapy (ERT) where the respective enzyme lacking in the patient is produced by recombinant approaches and then introduced into the blood stream, from where it is internalized by the cells and reaches the lysosomes replacing the missing endogenous enzyme. ERT products are on the market today for a number of LSD including Gaucher, Fabry, Pompe disease and the Mucopolysaccharidoses MPSI, II and VI and clinical trials are underway for a number of others. To date, no real treatment for alpha-Mannosidosis is available. Since children are born healthy, an early initiated therapy shortly after birth could dramatically improve their life expectancy and quality of life. Since pharmaceutical interest in this disease is low, two EU sponsored projects (EURAMAN and HUE-MAN) within the 5th and 6th framework program, respectively have worked towards developing the recombinant human enzyme (rhLAMAN) as a therapeutic agent for patients suffering from alpha-Mannosidosis and are now the basis for clinical trials in alpha-Mannosidosis. The enzyme has received Orphan Drug Designation in Europe in January 2005 (EU/3/04/260).


Project objectives

The main scientific objectives of ALPHA-MAN will be:

Objective 1:

Implementation of clinical trials in alpha-Mannosidosis patients to provide an effective drug for the orphan disease alpha-Mannosidosis.


Objective 2:

Determination of the minimal effective dose by chronic treatment studies in immune-tolerant alpha-Mannosidosis mice.


Objective 3:

Studies of the mechanism how recombinant human LAMAN crosses the Blood Brain Barrier.


Objective 4:

Studies of the impact on chronic ERT treatment on the neuropathology and underlying behavioural deficits in alpha-Mannosidosis mice.