Greater than 80 lysosomal proteins have been characterized, and mutations in genes encoding these proteins result in over 50 clinically distinct lysosomal storage diseases. Of these disorders, eight are due to the impaired degradation of glycosphingolipids. The traditional approach for treating these disorders has been through the use of mannose or mannose-6-phosphate terminated recombinant proteins as the basis for enzyme replacement therapy. An alternative approach, now clinically proven for the treatment of type 1 Gaucher disease, is the use of substrate reduction therapy. By targeting the first synthetic step in glycosphingolipid synthesis, catalyzed by glucosylceramide synthase, potent small molecule inhibitors have been developed as oral agents for the treatment of Gaucher type 1 and Fabry disease. One compound in the PDMP series, eliglustat tartrate, has been demonstrated to be at least as efficacious as imiglucerase in phase 2 and 3 trials and in August, 2014 was approved by the FDA for Gaucher disease type 1. Because eliglustat tartrate does not cross the blood brain barrier, it is unsuitable for the treatment of several glycosphingolipidoses with CNS involvement that include Gaucher disease type 3. Through the use property-based design, a series of analogues have been synthesized and demonstrated by in vitro and in vivo work to evade pgp1 and cross the blood brain barrier, effectively lowering brain glucosylceramide content in both normal and diseased mice. We now propose through the UH2/UH3 funding mechanism to optimize this compound and conduct further development for clinical trials for Gaucher disease type 3.
Specific aim 1 : We will conduct a one year UH2 preparatory and feasibility phase program that will establish a general investigative plan. The goals of this preparatory phase will include the identification and establishment of a lead development team, the establishment of a minimum acceptable profile to guide final lead optimization, the determination of the scope of enabling studies, and the identification of the academic laboratories or contractors that will perform these studies.
Specific aim 2 : The lead development team will conduct a multi-year UH3 development phase program that will include the final lead optimization of the CNS permeant glucosylceramide synthase inhibitor, the performance of biological testing and proof of concept studies in a suitable model of Gaucher disease type 3, development of a scalable, patentable synthetic route suitable for generation of the active pharmaceutical ingredient for good laboratory practice, toxicology studies, investigative new drug enabling studies, the design of phase one trials in healthy subjects.
The recent approval of eliglustat tartrate for the treatment of Gaucher disease demonstrates that drugs that inhibit the synthesis of glycolipids are viable alternative for the treatment of rare inherited diseases such as Gaucher disease type 1. A similar strategy is now proposed for Gaucher disease type 3 in which there is involvement of the brain. This approach will require the design and development of comparable drugs that distribute into the central nervous system.
| Shayman, James A; Tesmer, John J G (2018) Lysosomal phospholipase A2. Biochim Biophys Acta Mol Cell Biol Lipids : |
