Discovery of Critical Pathway

NGLY1 Deficiency is a devastating ultra-rare disease. Patients with this condition suffer from global developmental delay as well as motor and cognitive impairments. This disease results from a mutation in the N-glycanase 1 (NGLY1) gene, resulting in the inability to produce active NGLY1 enzyme.

Our team discovered that NGLY1 activity is required for the activation of a protein named NFE2L1 (also called NRF1).  This transcription factor is crucial for cellular health.

After discovering the NGLY1NFE2L1  link, our team quickly developed compounds that could address more common diseases in oncology and neurodegeneration.

Until now, NFE2L1 had been considered an “undruggable” target. With the discovery that NFE2L1 can be inactivated by targeting NGLY1, an enzyme which is a “druggable” target, we have revealed a completely novel way to modulate an several diseases.

NGLY1 Deficiency Infographic

NGLY1 Deficiency

We are pursuing multiple therapeutic modalities to treat NGLY1 Deficiency. By leveraging our knowledge of the NGLY1NFE2L1  connection, we started by finding small molecules to boost the activity of NFE2L1 and similar proteins. However, to arrive at a treatment for our patients as fast as possible, we are also pursuing several other therapeutic strategies, including gene therapy and enzyme-replacement therapy. Our philosophy is to take as many shots on goal as possible to increase the odds one will wind up on target.

  • Small Molecule

  • Gene Therapy

  • Enzyme Replacement Therapy

Our approach


Many cancer cells require optimal proteasome function to support their destructive functions. Some chemotherapies work by inhibiting the proteasome, causing the cancer cell to kill itself. However, cancer cells can sense this inhibition and combat the chemotherapies by activating the proteasome via the activation of NFE2L1 by NGLY1, making these two proteins an important axis in treating cancer.  We have an active oncology program to identify NGLY1 inhibitors that prevent cancer cells from reactivating.

  • Multiple Myeloma

  • Mantle Cell Lymphoma

  • Solid Tumors

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Rare Unlocks Common

Grace Science is leveraging NGLY1 biology to treat human disease.

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