Mucopolysaccharidosis type II (MPS II) is an X-linked recessive inherited disease caused by deficiency of the enzyme iduronate 2-sulfatase (IDS), resulting in lysosomal accumulation of glycosaminoglycans (GAGs) in various tissues, with subsequent multi-system pathology. A major manifestation of MPS II is severely stunted bone growth and skeletal deformities with significant pain and limitation of mobility. In the most severe form of MPS II, patients experience progressive neurocognitive impairment. Untreated, these patients typically die by age 10 due to cardiac or respiratory complications [1]. MPS II is currently treated by enzyme replacement therapy with idursulfase (Elaprase) or idursulfase beta (Hunterase). However, this therapy requires weekly 4-hour infusions – often beginning in infants and toddlers – and does not fully address the disease manifestations.

Immusoft’s proprietary technological platform, Immune System Programming (ISP™), involves programming B cells to deliver therapeutic proteins. B cells are differentiated towards plasma cells, the body’s most prolific biofactories. Immusoft is developing genetically engineered autologous human B cells for production of IDS for infusion into patients with MPS II. After differentiation into plasma blasts, the cells are infused back into the patients, where they fully differentiate into plasma cells and engraft in the bone marrow, the physiological niche for long-lived plasma cells. The Sleeping Beauty (SB) transposon system used for the engineering of B cells is a non-viral genetic engineering approach, and thus ISP™ B cells expressing IDS present an entirely novel approach for the treatment of MPS II. In non-clinical studies Immusoft has already demonstrated; (i) reliable SB-mediated IDS transposition and expression in primary human B cells in large-scale culture, and (ii) significant reduction of metabolic disease when these IDS-transposed plasma blasts (ISP-002) are adoptively transferred into immunodeficient NSGMPS II mice.

In the Tran1 project we demonstrated; 1) reliable SB-mediated IDS transposition and expression in primary human B cells on a clinical-scale, 2) significant reduction of metabolic disease when ISP-002 cells were adoptively transferred into immunodeficient NSG-MPS II mice. These results demonstrate the therapeutic potential of IDS-transposed B cells in MPS II and constitute essential results for pre-IND engagement with the FDA in the translation of this project toward clinical testing.

Our two  in vivo studies (milestones 1 and 3) demonstrated that doses of 2x1E+06 ISP-002 cells yield maximal reduction in metabolic disease and higher doses do not further increase efficacy. Moreover, we demonstrated that doses as low as 2x1E+05 ISP-002 cells reduced metabolic disease. Besides lowering pathogenic GAG accumulation in major tissues and elevating IDS enzyme activity, we also observed lower PYD levels – an indication that treatment had a beneficial effect on skeletal manifestations. No significant treatment-induced side effects were observed for any of treated animals, indicating excellent tolerability and safety. As part of two process development runs and two engineering runs (milestones 2 and 4, respectively), we successfully concluded stability assays for ISP-002. Finally, we are conducted a pre-IND meeting with the FDA to discuss the proposed strategy to advance ISP-002 to clinical trials (milestone 5).