Therapeutics

QRL-201

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Overview

Name: QRL-201
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 1)
Company: QurAlis Corporation

Background

QRL-201 is an antisense oligonucleotide targeting the mRNA of the STMN2 gene. This gene encodes stathmin-2, a microtubule-binding protein abundant in motor neurons and critical for axon stability. Errors in STMN2 transcript splicing lead to decreased protein expression and precipitate neurodegeneration in cases of amyotrophic lateral sclerosis and frontotemporal dementia. QRL-201 is designed to modulate splicing of the STMN2 mRNA to restore protein expression. It is delivered by injection into the spinal cord.

STMN2 expression is controlled by the RNA-binding protein TDP-43, which is found mislocalized and aggregated in most amyotrophic lateral sclerosis cases, and half of frontotemporal dementia cases. In cells without functioning TDP-43, STMN2 mRNA transcripts fail to splice properly or produce protein, leading to cell degeneration (Klim et al., 2019; Melamed et al., 2019). In preclinical work, an ASO that corrects STMN2 splicing restored protein expression in TDP-43-deficient human motor neurons, or in mice with misprocessed STMN2 mRNAs (Baughn et al., 2023). Studies with patient tissue found truncated STMN2 mRNA serves as a marker of TDP-43 pathology in motor neurons and brain tissue (Prudencio, et al., 2020; Pickles et al., 2022). 

Genetic studies identified a variant in STMN2 associated with ALS risk (Theunissen et al., 2021), but this finding was not replicated in independent cohorts (Ross et al., 2022; Grima et al., 2022; Doronzio et al., 2022).

Findings

In December 2022, QurAlis began a first-in-human Phase 1 safety and pharmacokinetics study of QRL-201. At three sites in Canada, the trial is enrolling 64 people with ALS in eight ascending dose cohorts, each randomized 6:2 to drug or placebo, administered by intrathecal injection. Sites in other countries are to be added; completion is anticipated in May 2025 (company press release).

For details on QRL-201 trials, see clinicaltrials.gov.

Last Updated: 15 May 2023

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References

Paper Citations

  1. Klim JR, Williams LA, Limone F, Guerra San Juan I, Davis-Dusenbery BN, Mordes DA, Burberry A, Steinbaugh MJ, Gamage KK, Kirchner R, Moccia R, Cassel SH, Chen K, Wainger BJ, Woolf CJ, Eggan K. ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat Neurosci. 2019 Feb;22(2):167-179. Epub 2019 Jan 14 PubMed.
  2. Melamed Z, López-Erauskin J, Baughn MW, Zhang O, Drenner K, Sun Y, Freyermuth F, McMahon MA, Beccari MS, Artates JW, Ohkubo T, Rodriguez M, Lin N, Wu D, Bennett CF, Rigo F, Da Cruz S, Ravits J, Lagier-Tourenne C, Cleveland DW. Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat Neurosci. 2019 Feb;22(2):180-190. Epub 2019 Jan 14 PubMed.
  3. Baughn MW, Melamed Z, López-Erauskin J, Beccari MS, Ling K, Zuberi A, Presa M, Gonzalo-Gil E, Maimon R, Vazquez-Sanchez S, Chaturvedi S, Bravo-Hernández M, Taupin V, Moore S, Artates JW, Acks E, Ndayambaje IS, Agra de Almeida Quadros AR, Jafar-Nejad P, Rigo F, Bennett CF, Lutz C, Lagier-Tourenne C, Cleveland DW. Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. Science. 2023 Mar 17;379(6637):1140-1149. Epub 2023 Mar 16 PubMed.
  4. Prudencio M, Humphrey J, Pickles S, Brown AL, Hill SE, Kachergus JM, Shi J, Heckman MG, Spiegel MR, Cook C, Song Y, Yue M, Daughrity LM, Carlomagno Y, Jansen-West K, de Castro CF, DeTure M, Koga S, Wang YC, Sivakumar P, Bodo C, Candalija A, Talbot K, Selvaraj BT, Burr K, Chandran S, Newcombe J, Lashley T, Hubbard I, Catalano D, Kim D, Propp N, Fennessey S, NYGC ALS Consortium, Fagegaltier D, Phatnani H, Secrier M, Fisher EM, Oskarsson B, van Blitterswijk M, Rademakers R, Graff-Radford NR, Boeve BF, Knopman DS, Petersen RC, Josephs KA, Thompson EA, Raj T, Ward M, Dickson DW, Gendron TF, Fratta P, Petrucelli L. Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia. J Clin Invest. 2020 Nov 2;130(11):6080-6092. PubMed.
  5. Pickles S, Gendron TF, Koike Y, Yue M, Song Y, Kachergus JM, Shi J, DeTure M, Thompson EA, Oskarsson B, Graff-Radford NR, Boeve BF, Petersen RC, Wszolek ZK, Josephs KA, Dickson DW, Petrucelli L, Cook CN, Prudencio M. Evidence of cerebellar TDP-43 loss of function in FTLD-TDP. Acta Neuropathol Commun. 2022 Jul 25;10(1):107. PubMed.
  6. Theunissen F, Anderton RS, Mastaglia FL, Flynn LL, Winter SJ, James I, Bedlack R, Hodgetts S, Fletcher S, Wilton SD, Laing NG, MacShane M, Needham M, Saunders A, Mackay-Sim A, Melamed Z, Ravits J, Cleveland DW, Akkari PA. Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype. Front Aging Neurosci. 2021;13:658226. Epub 2021 Mar 26 PubMed.
  7. Ross JP, Akçimen F, Liao C, Spiegelman D, Weisburd B, Dupré N, Dion PA, Rouleau GA, Farhan SM. Questioning the Association of the STMN2 Dinucleotide Repeat With Amyotrophic Lateral Sclerosis. Neurol Genet. 2022 Aug;8(4):e678. Epub 2022 Jul 13 PubMed.
  8. Grima N, Henden L, Fearnley LG, Rowe DB, D'Silva S, Pamphlett R, Adams L, Kiernan MC, Mazumder S, Timmins HC, Zoing M, Bahlo M, Blair IP, Williams KL. NEK1 and STMN2 short tandem repeat lengths are not associated with Australian amyotrophic lateral sclerosis risk. Neurobiol Aging. 2022 Aug;116:92-95. Epub 2022 May 22 PubMed.
  9. Doronzio PN, Lattante S, Marangi G, Martello F, Conte A, Bisogni G, Bernardo D, Patanella AK, Meleo E, Zollino M, Sabatelli M. Analysis of STMN2 CA repeats in italian ALS patients shows no association. Amyotroph Lateral Scler Frontotemporal Degener. 2022 Jul 23;:1-3. PubMed.

External Citations

  1. company press release
  2. clinicaltrials.gov

Further Reading

Papers

  1. Klim JR, Pintacuda G, Nash LA, Guerra San Juan I, Eggan K. Connecting TDP-43 Pathology with Neuropathy. Trends Neurosci. 2021 Jun;44(6):424-440. Epub 2021 Apr 5 PubMed.
  2. Mehta PR, Brown AL, Ward ME, Fratta P. The era of cryptic exons: implications for ALS-FTD. Mol Neurodegener. 2023 Mar 15;18(1):16. PubMed.
  3. de Majo M, Koontz M, Marsan E, Salinas N, Ramsey A, Kuo YM, Seo K, Li H, Dräger N, Leng K, Gonzales SL, Kurnellas M, Miyaoka Y, Klim JR, Kampmann M, Ward ME, Huang EJ, Ullian EM. Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology. Stem Cell Reports. 2023 Mar 14;18(3):706-719. Epub 2023 Feb 23 PubMed.
  4. Cao MC, Scotter EL. Transcriptional targets of amyotrophic lateral sclerosis/frontotemporal dementia protein TDP-43 - meta-analysis and interactive graphical database. Dis Model Mech. 2022 Sep 1;15(9) Epub 2022 Sep 13 PubMed.
  5. Ni W, Wang S, Cheng D, Song F. Focusing on in vivo and in vitro axonal-degeneration models optimization may better evaluate the role of STMN2. J Neurosci Res. 2023 Mar;101(3):295-297. Epub 2022 Dec 15 PubMed.