Metabolic diseases are inherited medical conditions that interfere with the body’s complex chemical reactions. Through the use of special enzymes, these chemical reactions include the production of energy, the breaking down of food or certain chemicals and for the breaking down of waste substances that the body no longer requires. Depending on the disorder, the failure of these chemical reactions can either deprive the body of sufficient quantities of substances (such as insulin) that it requires for normal good health or they can result in the excessive build-up of waste substances that can severely impair health, as with Lysosomal Storage Diseases.
Lysosomal Storage Diseases (“LSD”) are rare inherited metabolic diseases that are caused by a defective gene that results in an enzyme deficiency. These enzymes are usually found in cellular structures called lysosomes. Lysosomes are considered the “recycling unit” of the cell and are responsible for the disposal of unneeded molecules. Without these critical enzymes to break down waste in the lysosomes, toxic substances accumulate in the cells causing impairment of the cell’s normal functions. This results in cell death and eventually to organ and brain damage. There are over 50 known LSDs with an overall occurrence of 1 in 7000 live births.
Enzyme Replacement Therapy (“ERT”) is used to treat LSDs. However, replacement enzymes do not cross the blood-brain barrier, leaving the brain untreated for the diseases. Current treatments include invasive intrathecal methods of enzyme delivery. The delivery the enzymes through the BBB may allow more efficacious treatment for LSDs as well as a simpler and noninvasive means of administering the treatments.
The biOasis Transcend Platform is a group of proprietary technologies designed for the transport of a wide range of therapeutic agents across the blood-brain barrier for the treatment of many types of CNS disorders, including the delivery of enzymes for Lysosomal Storage Diseases.
A previous animal study showed that Transcend (MTf) is able to deliver to the brain the necessary enzyme for the treatment of the LSD, Hurler Syndrome or MPS I, and that the treatment restored enzyme activity in the brain towards normal wild levels in a dose-dependent manner.
Based on the results of this study, biOasis has established an in-house Lysosomal Storage Disease Program for the development of LSD therapeutics and for the advancement of the Transcend Platform.
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Study: Hurler Syndrome (MPS I)
Disease: Hurler Syndrome (MPSI)
Treatment: The enzyme, alpha-L-iduronidase (“IDU”)
Medical Problem: Mucopolysaccharidosis I (MPS I or Hurler Syndrome) is caused by a deficiency of the enzyme, alpha-L-iduronidase (“IDU”). Without this enzyme, the cells cannot break down long chains of sugar molecules called glycosaminoglycans (GAG), which ultimately accumulate in the lysosomes causing damage to cells in the brain and organs. When administered as a therapeutic, IDU is unable to cross the BBB, leaving the brain untreatable with normal Enzyme Replacement Therapy. In addition to severe physical symptoms throughout the body, Hurler Syndrome causes severe and progressive Intellectual disabilities starting from early childhood.
Transcend Therapeutic: Transcend (MTf) + α-L-iduronidase (“IDU”) chemical conjugate and fusion protein.
- MTf + IDU increased IDU brain enzyme activity approximately 4-fold.
- Dose-Dependent Increase in Brain Enzyme Activity in MPS I Knockout Mice With IV administered MTf + IDU.
- MTf + IDU restores IDU brain enzyme activity towards wild type levels in a dose-dependent fashion.
- Liver did contain significant amounts of expected activity 48 hours after the last injection.
Opportunity: Transcend + specific enzymes can cross the BBB, enter the brain cells, localize in the intracellular compartments (lysosomes) and become active, offering the promise of an LSD enzyme replacement CNS therapy.
Plan of Action
Based on the success of the Transcend and Hurler Syndrome study, as well as additional attributes of LSDs, biOasis has established a Lysosomal Storage Diseases Program for the advancement of the company’s Transcend Platform. The potential commercial markets for certain LSD therapies that require delivery to the brain are estimated to be almost $2 billion per year.
According to the Brains for Brain Foundation (“B4B”) of Padova, Italy, LSDs “…are the only group of pediatric neurodegenerative diseases for which therapy that can reverse the natural history of the disease in peripheral organs is available.” 1
The B4B Foundation goes on to state about LSDs, “…the advanced knowledge of the genetic and biochemical features responsible for the development of neurodegeneration along with excellent animal models in these diseases makes it possible to begin to decipher the cascade of pathological events leading to loss of brain plasticity and mental retardation.” 1
Pipeline Addition: MPS II (Hunter Syndrome)
biOasis has placed the LSD, MPS II (Hunter Syndrome), in its therapeutic pipeline with the September, 2014 announcement of the initiation of an MPS II study with the renowned Lysosomal Storage Disease expert, Dr. Maurizio Scarpa, and the Brains for Brain Foundation of Padova, Italy. The study will test the efficacy of MTfp-I2S (and MTf-I2S) for the treatment of MPS II in an animal model. The results of the study will be used to support the design of clinical studies to evaluate the efficacy of MTfp-I2S and MTf-I2S in MPS II patients.
Pipeline Addition: Sandhoff Disease
biOasis has also placed the LSD, Sandhoff Disease, in its therapeutic pipeline. In September, 2014, biOasis announced the initiation of a Sandhoff Disease study with The University of British Columbia’s, Dr. Wilfred Jefferies, biOasis’ founding scientist, of the university’s renowned Michael Smith Laboratories. The study will test the efficacy of MTfp-HEXB (and MTf-HEXB) for the treatment of Sandhoff Disease in an animal model. The results of the study will be used to support the design of clinical studies to evaluate the efficacy of MTfp-HEXB and MTf-HEXB in Sandhoff Disease patients.
biOasis believes that the treatment of Lysosomal Storage Diseases using the Transcend Platform offers important commercial opportunities for the company as well as the opportunity to prove the powerful and varied capabilities of the Transcend Platform for the treatment of CNS disorders.
1. Quotes from Brains for Brain Foundation of Padova, Italy: http://www.brains4brain.eu/research