|
|
| |
|
Home >> Science & Technology >> Chaperone-ERT Combinations
Chaperone-ERT Combinations
ERT: First-Generation Treatment for LSDs
ERT is the standard of care for several LSDs, which are caused by the deficiency of specific lysosomal enzymes. ERT is based on the intravenous infusion of recombinant or gene-activated human enzyme. The enzyme is delivered into the blood in order to reach specific receptor cell surfaces, to be taken up by cells and then transported to the lysosome. Upon entering the lysosome, this enzyme can perform the function of the unstable endogenous enzyme. However, the pH in the infusion bag and in blood is higher than the enzyme’s natural acidic environment in the lysosome. In result, the infused enzyme rapidly denatures and may be misdirected to non-target tissues or delivered in inactive form to the lysosome. Exposure to these infused enzymes may also mount an immune response or neutralizing antibodies than can impact efficacy or cause adverse effects.
Possible problems related to the unfolding of infused enzyme include:
-
Rapid denaturation and misfolding in blood, leading to short circulating half-life
- Immunogenicity
- Poor delivery and uptake of active enzyme into key tissues of disease
- Reduced activity
Chaperone-ERT Combinations: Next-Generation Approach for Lysosomal Storage Diseases (LSDs)
Preclinical studies suggest that chaperone-ERT co-administration and co-formulation may represent a new
approach for the treatment of LSDs. Animal models of Fabry, Pompe and Gaucher have shown that a pharmacological chaperone can selectively bind to and stabilize the infused enzyme, prevent its deactivation in the circulation, and increase uptake of active enzyme into key tissues of disease compared to ERT alone. In Fabry and Pompe animal models, this increased activity and tissue uptake has lead to greater substrate reduction than ERT alone.
Proposed Mechanism of Action
In combination with ERT, pharmacological chaperones are designed to bind to and stabilize infused enzyme in circulation as patients receive ERT. These chaperone-ERT combinations have the potential to improve the stability, uptake and activity of the infused enzyme, and may lower immunogenicity compared to ERT alone. This combination approach may benefit patients currently on ERT treatment, including patients with inactive endogenous proteins who are not amenable to chaperone monotherapy.
|
What's Missing in Lysosomal Storage Diseases?
(pdf - 1.6MB)
About Pharmacological Chaperones
(pdf - 640KB)
Glossary
|
|
|
|
|
