Two Target ALS funded consortia have now published work that could usher in the first ALS diagnostic biomarker. In partnership with Biogen, Phil Wong from Johns Hopkins University identified an extra piece of protein (“cryptic peptide”) present in the HDGFL2 protein. This cryptic peptide appears in the absence of functional TDP-43, an RNA-binding protein whose dysfunction is implicated in 97% of ALS cases. In a recent Nature Medicine publication, the consortium reported detection of this HDGFL2 cryptic peptide in postmortem tissue from individuals with ALS and FTLD, where it specifically appeared in neurons also lacking functional TDP-43. Further exploration of the HDGFL2 cryptic peptide in cerebrospinal fluid of individuals with familial and sporadic ALS revealed this cryptic peptide appears prior to ALS symptoms in people with the ALS and FTD-related C9orf72 repeat expansion and is also present in individuals with sporadic ALS.
Lending further support to the HDGFL2 cryptic peptide as a potential ALS biomarker is work recently published in Molecular Neurodegeneration and Science Translational Medicine from a Target ALS and Gates Foundation/ADDF funded consortium led by Pietro Fratta at UCL. Work from Len Petrucelli, Michael Ward, and Mercedes Prudencio confirms that the HDGFL2 cryptic peptide specifically appears in brain regions with TDP-43 pathology, lending support for specificity of the marker for TDP-43-positive forms of ALS and FTLD. Further work from this team suggests cryptic peptides due to loss of TDP-43 in other proteins could provide promise as additional diagnostic windows into ALS.
Pietro Fratta, Michael Ward, Mercedes Prudencio, and Len Petrucelli continue to hone detection of these HDGFL2 cryptic peptides. BioMarin, their industry partner, is developing a sensitive assay in the hopes of rigorously and repeatedly detecting the HDGFL2 cryptic peptide in the CSF and blood of people at risk for ALS. The identification of a specific target represents an important scientific milestone in biomarker development, and the detection of this cryptic peptide in presymptomatic individuals suggests that the HDGFL2 cryptic peptide has promise as a very early diagnostic tool. Given the life expectancy of 2-5 years following the onset of ALS symptoms, shortening the time to diagnosis would provide patients with an expanded window for therapeutic intervention, potentially dramatically improving quality of life and lifespan.
Cryptic peptide assays have the potential to broadly accelerate many aspects of drug discovery in ALS, from earlier diagnosis to measurement of target engagement in clinical trials. By supporting these innovative academic and industry collaborations, Target ALS is driving science forward, aligning with our mission to break down barriers to accelerate ALS research. As we continue to advance these efforts, we remain committed to our overall vision, Everyone Lives, working toward a future where ALS is no longer a terminal diagnosis but a manageable condition with improved outcomes for all.
Target ALS is thrilled to have supported these academic and industry partnerships so they could reach this major milestone.
