LINCLLate Infantile Neuronal Ceroid Lipofuscinosis
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Polaryx Therapeutics is solely dedicated to developing drug candidates for LINCL and other types of NCL for which there is currently no safe and patient-friendly treatment option available.
Additionally, LINCL is caused by mutations in the Cln2 gene that leads to the deficiency and/or loss of function of Tripeptidyl Peptidase 1 (TPP1) that leads to accumulation of autofluorescent storage materials in neurons and in other cells.
3) indicated that the activities in the DBS from the LINCL patients were significantly lower than the lowest normal values and also lower than the activities from patients affected by the other LSD.
[4] Nonstandard abbreviations: LSD, lysosomal storage disorders; DBS, dried blood spots; MS/MS, tandem mass spectrometry; TPP1, tripeptidyl peptidase 1; NAGLU, [alpha]-N-acetylglucosaminidase; GUSB, lysosomal [beta]-glucuronidase; IUDA, [alpha]-iduronidase; MPSs, mucopolysaccharidoses; I2S, iduronate-2-sulfatase; GALNS, N-acetylgalactosamine- 6sulfatase; ARSB, N-acetylgalactosamine-4-sulfatase; LINCL, infantile neuronal ceroid lipofuscinosis; ESI, electrospray ionization; LC, liquid chromatography; P, product; IS, internal standard; S, substrate; MRM, multiple reaction monitoring.
Mean activity ([micro]mol/h/L blood) (a) Sample GALNS NAGLU ARSB Blank (n = 6) 0.0033 0.01 0.05 CDC QC low (b) (n = 2) 0.17 0.23 0.46 CDC QC high (b) (n =2) 3.0 5.8 5.1 Adults (n = 4) 1.1 4.1 1.2 Newborns (n = 62) 0.67 1.6 4.4 MPS IIIB patients (n =4) 0.83 0.01 1.7 MPS VII patients (n =3) 1.0 3.2 1.8 LINCL patients (n = 7) 1.2 3.1 1.8 Mean activity ([micro]mol/h/L blood) (a) Sample I2S GUSB TPP1 Blank (n = 6) 0.06 0.06 0.03 CDC QC low (b) (n = 2) 0.98 13.0 5.0 CDC QC high (b) (n =2) 14.6 44.4 22.7 Adults (n = 4) 17.0 19.5 19.0 Newborns (n = 62) 16.1 28.5 35.9 MPS IIIB patients (n =4) 19.2 17.7 21.2 MPS VII patients (n =3) 26.1 0.08 20.4 LINCL patients (n = 7) 17.1 27.0 1.3 (a) For SDs in these measurements see online Supplemental Table 2.
We developed a diagnostic assay (termed "pepinase", for pepstatin-insensitive protease) based on the ability of specimens from healthy individuals but not patients with LINCL to degrade hemoglobin into trichloroacetic acid-soluble products in the presence of aspartyl and cysteinyl protease inhibitors (8).
However, to date the TPP-I assay has been applied only to cultured fibroblasts, with the TPP-I activity of LINCL fibroblasts being ~5% of healthy controls (10).
(8)], all 51 specimens analyzed (representing leukocytes, cultured cells, or brain autopsy specimens from 46 different LINCL families) could easily be discriminated from carriers and controls.
All 80 samples from healthy controls, LINCL carriers, and patients with other neurological diseases had robust activity.