The long-term goal of this project is to develop an improved ERT for MPS I patients with innovations that enhance ERT delivery and disease correction in hard to treat organs such as the brain while integrating safety and cost advantages of plant-based bioproduction. MPS I Syndrome is caused by genetic deficiencies in the lysosomal enzyme ?-L-iduronidase (IDUA). While current ERT drug options for MPS I effectively treat many visceral organs, significant debilitating manifestations of this disease in the central nervous system (CNS) remain to be addressed. Previous cellular studies by BioStrategies showed that this lectin, which has high affinity for glycoproteins and glycolipids common on mammalian cell surfaces, can mediate efficient cellular uptake, transcytosis, and delivery of IDUA to lysosomes. In vitro analyses of MPS I patient fibroblasts treated with our IDUA-Lectin fusion (termed IDUAL) demonstrated rapid and efficient correction of cellular disease phenotypes. Our Phase I feasibility animal studies on this project have shown that IDUAL could be delivered to the brains of MPS I mouse model animals yielding correction of both cellular and behavioral phenotypes of this disease and achieving the milestone objectives of the Phase I study.
Specific aims for this follow-up Phase II proposal are 1) Assess in vivo drug dosage levels, frequency, and CNS drug delivery and efficacy readouts in MPS I mice, 2) Develop IDUAL product scale-up, stability, and qualification protocols to support advanced preclinical studies, and 3) Establish rigorous preclinical animal data assessing efficacy, age at treatment onset, immunogenicity, gender effects, and behavioral correction following long-term IDUAL administration. Achievement of phase I goals of this project showing in vivo cellular and behavioral animal efficacy of IDUAL has provided a critical proof-of-concept for our lectin carrier ERT fusion drug delivery technology. The overall goal of this Phase II renewal project will be to complete the next stage of drug production scale-up, and highly rigorous animal studies that will lay a solid foundation for the follow-up preclinical research that will be required to support a successful IND application for initiating clinical trails. Furtherance of our successful proof-of concept studies on this project will build a solid basis for potential applications of this lectin based drug delivery technology platform to a wide variety of other previously hard to treat diseases.
The family of human genetic diseases represented by MPS I and other lysosomal disorders (LDs) include some of the most devastating human afflictions known and the most costly to patients, their families, and the public health system. The currently approved enzyme replacement therapeutics (ERTs) available to treat several of these diseases, although effective for many patients, still suffer from problems of safety, high cost, availability of adequate product supplies to patient populations, and product effectiveness in treating all organs of body. The new therapeutics technologies for MPS I developed in this SBIR Phase II R&D project would address all of these issues by employing new drug delivery technology that more effectively targets affected cell types, cellular compartments, and organs. The need for delivering these new treatment options for treating the central nervous system (CNS) and brain is particularly critical as current drug options for LDs are generally not effective in the brain. The innovative drug delivery technology developed in this project including our use of cheaper plant-based manufacturing would further the national goal of reducing the suffering and costs for patients afflicted with MPS I and others of these devastating genetic diseases.
