Gene therapy for cross-correction of somatic organs and the CNS in mucopolysaccharidosis II in rodents and non-human primates

Nancy Chen; David E Ehmann; Robert Crooker; Katayoun Derakhchan; Xiaodong Fang; Brian Felice; Elizabeth J Galbreath; Charles Glaus; Hongbo Gu; Yan Huang; Christine Li; Xing Li; Nan Liu; Kathleen Palmieri; Damir Simic; Joseph Sypek; Susan Thompson; Christopher T Winkelmann; Vivian W Choi

doi:10.1016/j.omtm.2023.03.014

Gene therapy for cross-correction of somatic organs and the CNS in mucopolysaccharidosis II in rodents and non-human primates

Mol Ther Methods Clin Dev. 2023 Mar 28:29:286-302. doi: 10.1016/j.omtm.2023.03.014. eCollection 2023 Jun 8.

Authors

Nancy Chen¹, David E Ehmann^{1

2}, Robert Crooker¹, Katayoun Derakhchan¹, Xiaodong Fang^{1

3}, Brian Felice¹, Elizabeth J Galbreath¹, Charles Glaus^{1

4}, Hongbo Gu^{1

5}, Yan Huang^{1

6}, Christine Li¹, Xing Li^{1

7}, Nan Liu¹, Kathleen Palmieri¹, Damir Simic^{1

8}, Joseph Sypek¹, Susan Thompson¹, Christopher T Winkelmann¹, Vivian W Choi¹

Affiliations

¹ Takeda Development Center Americas, Inc., Cambridge, MA, USA.
² Pretzel Therapeutics, Waltham, MA, USA.
³ Asklepios BioPharmaceutical (AskBio), Research Triangle Park, NC, USA.
⁴ Bayer HealthCare Pharmaceuticals, Cambridge, MA, USA.
⁵ PTM Bio LLC, Hangzhou, Zhejiang, China.
⁶ Editas Medicine, Cambridge, MA, USA.
⁷ Ultragenyx, Cambridge, MA, USA.
⁸ Astellas Gene Therapies, San Francisco, CA, USA.

Abstract

Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by deficient activity of iduronate-2-sulfatase (I2S), leading to pathological accumulation of glycosaminoglycans (GAGs) in tissues. We used iduronate-2-sulfatase knockout (Ids KO) mice to investigate if liver-directed recombinant adeno-associated virus vectors (rAAV8-LSP-hIDS_co) encoding human I2S (hI2S) could cross-correct I2S deficiency in Ids KO mouse tissues, and we then assessed the translation of mouse data to non-human primates (NHPs). Treated mice showed sustained hepatic hI2S production, accompanied by normalized GAG levels in somatic tissues (including critical tissues such as heart and lung), indicating systemic cross-correction from liver-secreted hI2S. Brain GAG levels in Ids KO mice were lowered but not normalized; higher doses were required to see improvements in brain histology and neurobehavioral testing. rAAV8-LSP-hIDS_co administration in NHPs resulted in sustained hepatic hI2S production and therapeutic hI2S levels in cross-corrected somatic tissues but no hI2S exposure in the central nervous system, perhaps owing to lower levels of liver transduction in NHPs than in mice. Overall, we demonstrate the ability of rAAV8-LSP-hIDS_co to cross-correct I2S deficiency in mouse somatic tissues and highlight the importance of showing translatability of gene therapy data from rodents to NHPs, which is critical for supporting translation to clinical development.

Keywords: AAV; Hunter syndrome; MPS II; cross-correction; gene therapy; iduronate-2-sulfatase; lysosome; non-human primates.