USE OF NEW PHARMACOLOGICAL CHAPERONES FOR THE TREATMENTOF LYSOSOMAL STORAGE DISORDERS - CF4Lyso

BACKGROUND: Fabry Disease (FD) is considered a rare disease (incidence ~1:7.000 calculated in neonatal screening) included in the group of Lysosomal Storage Disorders (LSD) and new treatments for these pathologies are generally designated as orphan drugs. FD (OMIM # 301500) is a hereditary pathology linked to the X chromosome and caused by a deficiency of α-GalA, a hydrolytic enzyme expressed in the lysosomes. The current treatments of FD, Enzyme Replacement Therapy (ERT), have important limitations, such as a high cost of production, the bioavailability, the inmunogenicity, or the administration. Pharmacologial Chaperones (CPs) are the most promising alternative to improve treatments in FD and LSDs. PCs are small molecules, for possible oral administration, useful in patients with mutations that affect the folding of the protein. However, the main limitation of the only CP authorized for the treatment of FD (Galafold®) and other CPs under study is that these compounds are only useful with enzymes mutations affect the stability of the protein compromising its correct folding, and its effectiveness may be higher or lower depending on the specific mutation. Also, the current available CFs have a narrow range of therapeutic concentration, since in excess they can act as inhibitor of α-GalA competing with its natural substrate.

The challenge of researchers in this field is focused on the developmentof new prototypes that act as α-GalA stabilizers and that beactiveinasmany mutations as possible.

ACHIEVEMENT AND RESULTS: A new family of galactose analogues (PBX) is proposed as apossibletreatment of FD and other LSDs. PBX acts as stabilizer of theα-GalAinthe presence of mutations that affect its folding.

PURPOSES AND ADVANTAGES: PBX can bind to the active site of α-GalA and stabilize its structuretoconsequently increase its enzymatic activity. The main advantages of this family of compounds are:  In comparison with ERT therapies, PBX has a homogeneousdistribution, since they are small molecules, capabletocrossbiological membranes, including blood-brain barrier.  PBX has the ability of binding to the mutated α-GalAenzymesresponsible of FD which are not possible to treat withthePCcurrently in use, increasing the therapeutic spectrumof thepatientswho can use the oral treatment.  The PCs are chemical molecules so their production cost andriskofcontamination are significantly lower than the productioncostofERT, whose drugs are biological.

COLLABORATION OFFER: This offer can be materialized in a “Partnership Agreement” inordertoco-develop this technology or in a “License Agreement” for usingusetheproposed technology directly. If this offer is of your interest or youneedmore information about, please contact us.