Science & Technology

Platform Technologies

Our technologies are intended to stabilize proteins with either a pharmacological chaperone on its own or a novel Enzyme Replacement Therapy in combination with a chaperone.

Protein Misfolding in Lysosomal Storage Disorders (LSDs)

Lysosomal Storage Disorders (LSDs) result from mutations in specific lysosomal enzymes, proteins that function in the lysosomal compartment to degrade molecules (substrates) into smaller pieces that can be used to build new molecules. Mutations in a patient’s own (endogenous) lysosomal enzyme may lead to a decrease in the protein’s stability, and even misfolding or unfolding of the enzyme. Unstable, unfolded, or misfolded lysosomal enzymes are generally not efficiently transported to their intended destination in the cell (ie., the lysosome) to degrade substrate. This complete or partial loss of protein function and enzymatic activity may lead to several problems, including:

  • Substrate accumulation;
  • Disruption of cellular function; and
  • Cell death.

Treatment

Treatment for LSDs by intravenous infusion of recombinant or gene-activated human enzyme is intended to deliver a therapeutic protein into the blood in order to be taken up by cells and then transported to the lysosome. Upon entering the lysosome, this enzyme is intended to perform the function of the absent or deficient endogenous enzyme. However, the pH in the infusion bag and in blood is higher than the enzyme's natural acidic environment in the lysosome. As a result, the infused enzyme may unfold and lose activity and may be misdirected to non-target tissues or rapidly cleared from the body. Possible problems related to the instability of infused enzyme include:

  • Denaturation and reduced activity;
  • Poor targeting and uptake into key tissues of disease; and
  • Poor tolerability and increased immunogenicity.

We are developing a pharmacological chaperone technology to treat LSDs that are characterized by mutated proteins that are unstable, unfolded, or misfolded. Pharmacological chaperones are small molecules designed to selectively bind to a target enzyme to potentially increase its stability and help keep it folded in the correct three-dimensional shape. For LSDs, pharmacological chaperones are designed to bind to, and facilitate trafficking of, both endogenous and exogenous enzymes to the location in cells where they are needed, i.e., the lysosomes.

Lysosomal Storage Disorders result from mutations in specific lysosomal enzymes, proteins that function in the lysosomal compartment to degrade molecules (substrates) into smaller pieces that can be used to build new molecules. Mutations in a patient’s own (endogenous) lysosomal enzyme may lead to a decrease in the protein’s stability, and even misfolding or unfolding of the enzyme. Unstable, unfolded, or misfolded lysosomal enzymes are generally not efficiently transported to their intended destination in the cell (ie., the lysosome) to degrade substrate. This complete or partial loss of protein function and enzymatic activity may lead to several problems, including:

  • Substrate accumulation;
  • Disruption of cellular function; and
  • Cell death.

We are leveraging our proprietary CHART™ technology to develop chaperone/ERT combinations that may benefit patients with LSDs. In each CHART™ program, a unique pharmacological chaperone is designed to bind to a specific therapeutic (exogenous) enzyme, stabilizing the enzyme in its properly folded and active form.