2. Academic Validation
  3. Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency

Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency

  • ACS Chem Biol. 2024 Oct 17. doi: 10.1021/acschembio.4c00571.
Lara N Gechijian 1,  Giovanni Muncipinto 2,  T Justin Rettenmaier 1,  Matthew T Labenski 1,  Victor Rusu 3,  Lea Rosskamp 1,  Leslie Conway 1,  Daniel van Kalken 1,  Liam Gross 4,  Gianna Iantosca 5,  William Crotty 6,  Robert Mathis 1,  Hyejin Park 1,  Benjamin Rabin 7,  Christina Westgate 8,  Matthew Lyons 9,  Chloe Deshusses 10,  Nicholas Brandon 6,  Dean G Brown 1,  Heather S Blanchette 1,  Nicholas Pullen 11,  Lyn H Jones 12,  Joel C Barrish 13
Affiliations

Affiliations

  • 1 Jnana Therapeutics, Boston, Massachusetts 02210, United States.
  • 2 Third Harmonic Bio, Cambridge, Massachusetts 02139, United States.
  • 3 Apple Tree Partners, New York, New York 10169, United States.
  • 4 Oregon State University, Portland, Oregon 97331, United States.
  • 5 Atavistik Bio, Cambridge, Massachusetts 02140, United States.
  • 6 Neumora Tx, Watertown, Massachusetts 02472, United States.
  • 7 Brigham and Women's Hospital, Boston, Massachusetts 02115, United States.
  • 8 DG Medicines, Boston, Massachusetts 02115, United States.
  • 9 University of California, San Francisco, California 90095, United States.
  • 10 University of North Carolina, Chapel Hill, North Carolina 27599, United States.
  • 11 ArtBio, Cambridge, Massachusetts 02139, United States.
  • 12 Center for Protein Degradation, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 13 RA Capital Ventures, Boston, Massachusetts 02116, United States.
PMID: 39418577 DOI: 10.1021/acschembio.4c00571
Abstract

Mutations in creatine transporter SLC6A8 cause creatine transporter deficiency (CTD), which is responsible for 2% of all cases of X-linked intellectual disability. CTD has no current treatments and has a high unmet medical need. Inspired by the transformational therapeutic impact of small molecule "correctors" for the treatment of cystic fibrosis, which bind to mutated versions of the CFTR ion channel to promote its trafficking to the cell surface, we sought to identify small molecules that could stabilize SLC6A8 as a potential treatment for CTD. We leveraged a novel chemoproteomic technology for ligand discovery, reactive affinity probe interaction discovery, to identify small-molecule fragments with photoaffinity handles that bind to SLC6A8 in a cellular environment. We synthesized a library of irreversible covalent analogs of these molecules to characterize in functional assays, which revealed molecules that could promote the trafficking of mutant SLC6A8 variants to the cell surface. Further medicinal chemistry was able to identify reversible drug-like small molecules that both promoted trafficking of the transporter and also rescued creatine uptake. When profiled across the 27 most prevalent SLC6A8 missense variants, we found that 10-20% of patient mutations were amenable to correction by our molecules. These results were verified in an endogenous setting using the CRISPR knock-in of selected missense alleles. We established in vivo proof-of-mechanism for correctors in a novel CTD mouse model with the P544L patient-defined variant knocked in to the SLC6A8 locus, where treatment with our orally bioavailable and brain penetrant tool corrector increased brain creatine levels in heterozygous female mice, validating correctors as a potential therapeutic approach for CTD.

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