The ALPHA MAN Project
Clinical development of Enzyme Replacement Therapy in alpha-Mannosidosis patients using recombinant human enzyme.
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).
The main scientific objectives of ALPHA-MAN will be:
Implementation of clinical trials in alpha-Mannosidosis patients to provide an effective drug for the orphan disease alpha-Mannosidosis.
- The aim of this study is to perform clinical trial Phases I, II and III in patients to demonstrate the safety and clinical efficacy of rhLAMAN as an effective therapeutic agent for treatment of the human disease alpha-Mannosidosis.
Determination of the minimal effective dose by chronic treatment studies in immune-tolerant alpha-Mannosidosis mice.
- The aim of this study is to find the minimal effective dose for a maximal correction of visceral and central nervous system pathology.
- Immune-tolerant alpha Mannosidosis mice will be chronically injected once a week with different doses of rhLAMAN and analysed for their storage in visceral and central nervous tissues.
Studies of the mechanism how recombinant human LAMAN crosses the Blood Brain Barrier.
- The aim of this study is to find putative receptors that are responsible for rhLAMAN uptake into the brain across the Blood Brain Barrier.
- Immune-tolerant alpha-Mannosidosis mice will be injected with high doses rhLAMAN and analysed for binding partners by various biochemical methods.
Studies of the impact on chronic ERT treatment on the neuropathology and underlying behavioural deficits in alpha-Mannosidosis mice.
- The aim of this study is to see whether long-term ERT treatment can prevent and/or reverse the neuropathology and associated behavioural deficits observed in immune-tolerant alpha-Mannosidosis mice.
- Immune-tolerant alpha-Mannosidosis mice will be chronically injected with the minimal effective dose (see Objective 2) and analysed for their neuropathology by either immuno-histological/biochemical or behavioural assays.