Preclinical Efficacy of Subcutaneous Enzyme Therapy for Lysosomal Fabry Disease

Project Summary
Fabry disease is a rare inherited genetic disorder that is estimated to affect 1 in every 40,000 to 117,000
people. It is characterized by a deficiency of GLA enzymes (α-galactosidase A) that leads to harmful buildup of
glycolipids in all tissues, causing disabling multi-organ disease and life-threatening complications over time.
Enzyme replacement therapy (ERT) in the form of intravenous GLA enzyme infusions has advanced Fabry
disease care. Although clinically effective, current ERT treatment requires frequent, life-long intravenous
infusions that are highly burdensome for patients. For example, in adults, biweekly peripheral venous injections
lead to lost productivity and potential vein damage. Meanwhile, in children, surgical placement of infusion ports
risks infection, restricts daily physical activities, and may lead to social anxiety and discrimination. These
burdens diminish patient quality of life, discourage early treatment initiation, and limit wider adoption.
Currently, various treatments such as biosimilars, modified ERTs, inhibitors, and gene therapy, are being
developed to improve therapeutic experience. However, the majority of emerging treatments still use the
intravenous format and provide few additional patient and cost benefits. Among prospective treatments, gene
therapy has shown the most promise. But recent clinical trials of viral gene therapies have resulted in
concerning side effects and inconsistent clinical efficacy, which diminishes the overall prospects of this
approach. Therefore, given the unclear outlook of emerging treatments, it is critical to develop more practical
and reliable therapies that improve the well-being of all Fabry patients.
Kinetiq is developing a pen-injector subcutaneous ERT for Fabry disease to reduce treatment burden and
expand patient accessibility. This self-administrable therapy will transform ERT into a convenient outpatient
treatment and significantly enhance patient quality of life, lower hospital use, and reduce treatment costs. As
part of our initial product development efforts, we demonstrated that our subcutaneous ERT (named BrySQ)
was favorably absorbed under physiological conditions into key body organs in healthy rodents.
In this SBIR Phase I proposal, we will conduct therapeutic feasibility studies of BrySQ in Fabry disease mice.
Following BrySQ intervention, we will evaluate drug distribution in heart and kidney tissues (Aim 1) and
quantify the resulting glycolipid reduction efficacy (Aim 2) using histology and mass spectrometry methods.
Once feasibility is established, we plan to conduct additional studies in a future SBIR Phase II study to
evaluate BrySQ doses and their corresponding safety, immunogenicity, kinetics, and efficacy. The successful
development of our BrySQ approach could potentially transform the current standard of care for Fabry and
other lysosomal diseases (e.g., Gaucher, Hurler, Hunter, Morquio, and Maroteaux-Lamy) while building upon
the safety and efficacy of ERT technology.

Grant Number: 1R43TR005111-01
NIH Institute/Center: NIH
Principal Investigator: Mingju Cao