Background of Enzyme Replacement Therapy for Lysosomal Storage Diseases
Lysosomal storage disorders (LSDs) are a heterogeneous group of inherited metabolic diseases. The most common pathogenic mechanism is a qualitative or quantitative deficiency of one of the 50 known lysosomal enzymes involved in the catabolism of multiple molecules. Deficiency of these enzymes leads to accumulation of substrates in connective tissues, skeletal structures and organs, resulting in progressive damage. As knowledge of lysosomal biology advanced, scientists proposed as early as 1964 that LSDs could be treated by replacing the defective enzyme with its normal counterpart. Enzyme replacement therapy (ERT) was the most important advance and major breakthrough in LSDs treatment. This approach is based on the regular intravenous infusion of human recombinant lysosomal enzymes. These enzymes bind to mannose or mannose-6-phosphate receptors available on the cytoplasmic membrane. As a result, the enzymes are internalized by the cells and delivered to the lysosomes via the endocytic pathway.
Fig. 1. Current treatment options and novel nanotechnology-driven enzyme replacement strategies for lysosomal storage disorders. (Del Grosso A, et al., 2022)
Solutions
The principle of ERT is to replace the specific defective enzyme in LSDs patients with a functional enzyme synthesized in vitro. Furthermore, LSDs represent the best model of an inherited metabolic disorder that can be treated by supplying the deficient enzyme from an external source. Our team of experts with extensive knowledge of lysosomal biology has successfully mastered ERT technology, and is dedicated to the development and evaluation of enzyme substitutes for LSDs. Our ERT platform successfully overcame two major early barriers to ERT: the lack of sufficient quantities of human enzymes and the need for animal models for preclinical studies.
With years of experience in drug development strategies for lysosomal storage diseases, CD BioSciences offers customized ERT solutions for LSDs.
Production of Recombinant Human Enzymes
While many proteins can be produced in large quantities in prokaryotic systems, efficient prokaryotic systems are also not available for lysosomal enzyme expression. We develop expression systems for CHO, human fibrosarcoma cells, transgenic animals, ova, and plant cells to produce therapeutic human lysosomal enzymes. In addition, our scientists ensure the production of sufficient amounts of human enzymes by cloning the cDNA and genes encoding human lysosomal enzymes.
Generation of LSD Mouse Models and Preclinical Studies of Enzyme Replacement Therapy
We use gene targeting techniques to generate mouse models, most of which have at least some biochemical, pathological and/or clinical manifestations of their human counterparts. In addition, our LSD researchers develop new methods to provide a large number of recombinant enzymes and disease-specific animal models for robust ERT development and evaluation. Importantly, preclinical studies in animal models allow for evaluation of the pharmacokinetics and pharmacodynamics of ERT for LSD.
Novel Nanotechnology-Driven Enzyme Replacement Strategies
Our scientists develop a new generation of ERT in an attempt to produce a more stable recombinant enzyme. Our strategy allows loading the enzyme into biodegradable nanomaterials to enhance the efficacy of ERT and minimize adverse effects. The following competitive advantages are offered:
❖ Encapsulating the enzyme into biocompatible liposomes, micelles and polymeric nanoparticles protects enzyme activity and eliminates immune reactions and premature enzyme degradation.
❖ Drugs that allow controlled release of the payload, improving pharmacokinetics and pharmacodynamics.
❖ The potential to functionalize nanocarrier surfaces with targeting agents (antibodies or peptides) can facilitate passage through biological barriers.
Why We Choose to Prepare Human Recombinant Lysosomal Enzymes in CHO Cells?
Most of the human recombinant lysosomal enzymes we develop are prepared in CHO cells, which have the following advantages:
- CHO cells have the post-translational modifications required for lysosomal enzyme stability, synthesis and/or activity.
- CHO cells are easy to grow and undergo post-translational modifications almost identical to those of human cells.
- Overexpression of lysosomal cDNA in CHO cells results in delivery of the encoded recombinant human enzyme to the lysosome.
- Most of the recombinant enzymes are selectively secreted into the media of the culture, thereby facilitating large-scale production of critical, highly glycosylated enzymes.
CD BioSciences' mission is to provide preclinical enzyme replacement therapeutic strategies for lysosomal storage diseases that provide new ideas for drug discovery. We look forward to collaborating with you in the discovery of innovative LSD therapeutic strategies. If you are interested in our solutions, please feel free to contact us.
Reference
- Del Grosso A, et al. (2022) Current treatment options and novel nanotechnology-driven enzyme replacement strategies for lysosomal storage disorders[J]. Advanced Drug Delivery Reviews. 2022: 114464.