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 a-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.