The present invention provides PEGylated aspartyl-tRNA synthetase (DRS) polypeptides, compositions comprising the same, and methods of using such polypeptides and compositions for treating or diagnosing a variety of conditions. The PEGylated DRS polypeptides of the invention have improved controlled release properties, stability, half-life, and other pharmacokinetic properties compared to non-PEGylated DRS polypeptides.

Isolated aspartyl-tRNA synthetase polypeptides and polynucleotides having non-canonical biological activities are provided, as well as compositions and methods related thereto.

The present invention provides aspartyl-tRNA synthetase and Fc region conjugate polypeptides (DRS-Fc conjugates), such as DRS-Fc fusion proteins, compositions comprising the same, and methods of using such conjugates and compositions for treating or diagnosing a variety of conditions. The DRS-Fc conjugates of the invention have improved controlled release properties, stability, half-life, and other pharmacokinetic and biological properties relative to corresponding, unmodified DRS polypeptides.

Isolated polypeptides comprising or consisting essentially of specific structural motifs (e.g., three -sheets and two -helices) are provided, wherein the polypeptides exhibit at least one cell signaling and/or other non-canonical activity of biological relevance. Also provided are polynucleotides encoding such polypeptides, binding agents that bind such polypeptides, analogs, variants and fragments of such polypeptides, etc., as well as compositions and methods of identifying and using any of the foregoing.

Provided herein are methods of treating leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) in a subject in need thereof, the method comprising: administering an adeno-associated virus (AAV) vector to the subject, wherein the adeno-associated vector increases expression of a DARS2 gene, thereby treating LBSL.