Recombinant Human GAL9C protein

GALC (galactocerebrosidase) is a lysosomal enzyme critical for hydrolyzing specific galactolipids, including galactocerebroside and psychosine, into ceramide and galactose. Deficiencies in GALC activity due to genetic mutations cause Krabbe disease (globoid cell leukodystrophy), a rare neurodegenerative disorder characterized by psychosine accumulation, demyelination, and severe neurological decline. Traditional therapeutic approaches for Krabbe disease remain limited, with hematopoietic stem cell transplantation showing partial efficacy only in pre-symptomatic cases.

Recombinant GALC protein has emerged as a promising therapeutic candidate for enzyme replacement therapy (ERT). Produced via mammalian cell lines (e.g., CHO cells) or microbial systems, recombinant GALC aims to restore enzymatic activity and reduce toxic psychosine levels. Early preclinical studies demonstrated its ability to cross the blood-brain barrier when administered intravenously or intrathecally, though delivery efficiency remains a challenge. A 2016 study using a human GALC variant produced in AAV-293 cells showed extended survival and reduced neuroinflammation in murine models.

Clinical translation faces hurdles such as immune responses against the exogenous enzyme and the need for repeated dosing. To address this, PEGylation or nanoparticle-based delivery systems are being explored to enhance stability and targeting. Recent phase I/II trials (e.g., NCT04693598) evaluate intrathecal recombinant GALC in infantile Krabbe patients, with preliminary data suggesting tolerability and slowed disease progression. Parallel research investigates gene therapy vectors (AAVrh10-GALC) as a complementary one-time treatment. Despite challenges, recombinant GALC represents a cornerstone in developing precision therapies for lysosomal storage disorders, bridging gaps between palliative care and disease modification.

**Background of GAL9C Recombinant Protein**

Galectin-9 (GAL9), a member of the galectin family, is a β-galactoside-binding lectin involved in diverse biological processes, including immune regulation, inflammation, and cancer progression. It exists in multiple isoforms due to alternative splicing, with GAL9C (C-terminal domain of galectin-9) representing a truncated form that retains functional activity. Structurally, galectin-9 contains two carbohydrate recognition domains (CRDs) connected by a linker peptide. GAL9C typically refers to the isolated C-terminal CRD, which maintains ligand-binding capabilities but lacks the N-terminal domain, potentially altering its functional properties compared to full-length galectin-9.

As a recombinant protein, GAL9C is produced via genetic engineering in systems like *E. coli* or mammalian cells, ensuring high purity and consistency for research applications. Its recombinant form enables precise study of galectin-9's domain-specific roles, particularly in immune modulation. GAL9C interacts with ligands such as Tim-3 (T-cell immunoglobulin mucin-3), a receptor expressed on immune cells, triggering downstream signals that regulate T-cell exhaustion, apoptosis, and tolerance. This interaction positions GAL9C as a critical player in autoimmune diseases, viral infections (e.g., HIV, hepatitis), and cancer immunotherapy.

In cancer, GAL9C exhibits dual roles: it may suppress antitumor immunity by promoting immunosuppressive microenvironments or enhance immune responses depending on context. Its recombinant version is explored therapeutically to modulate immune checkpoints or synergize with other agents. Additionally, GAL9C contributes to fibrosis and metabolic disorders, highlighting its broad biomedical relevance. Current research focuses on optimizing its structure-activity relationships and evaluating its therapeutic potential in preclinical and early clinical studies.