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Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice.
Ullman, Julie C; Arguello, Annie; Getz, Jennifer A; Bhalla, Akhil; Mahon, Cathal S; Wang, Junhua; Giese, Tina; Bedard, Catherine; Kim, Do Jin; Blumenfeld, Jessica R; Liang, Nicholas; Ravi, Ritesh; Nugent, Alicia A; Davis, Sonnet S; Ha, Connie; Duque, Joseph; Tran, Hai L; Wells, Robert C; Lianoglou, Steve; Daryani, Vinay M; Kwan, Wanda; Solanoy, Hilda; Nguyen, Hoang; Earr, Timothy; Dugas, Jason C; Tuck, Michael D; Harvey, Jennifer L; Reyzer, Michelle L; Caprioli, Richard M; Hall, Sejal; Poda, Suresh; Sanchez, Pascal E; Dennis, Mark S; Gunasekaran, Kannan; Srivastava, Ankita; Sandmann, Thomas; Henne, Kirk R; Thorne, Robert G; Di Paolo, Gilbert; Astarita, Giuseppe; Diaz, Dolores; Silverman, Adam P; Watts, Ryan J; Sweeney, Zachary K; Kariolis, Mihalis S; Henry, Anastasia G.
Afiliación
  • Ullman JC; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Arguello A; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Getz JA; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Bhalla A; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Mahon CS; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Wang J; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Giese T; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Bedard C; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Kim DJ; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Blumenfeld JR; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Liang N; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Ravi R; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Nugent AA; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Davis SS; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Ha C; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Duque J; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Tran HL; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Wells RC; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Lianoglou S; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Daryani VM; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Kwan W; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Solanoy H; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Nguyen H; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Earr T; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Dugas JC; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Tuck MD; Mass Spectrometry Research Center, Vanderbilt University, 9160 MRB III, 465 21 Avenue South, Nashville, TN 37240, USA.
  • Harvey JL; Mass Spectrometry Research Center, Vanderbilt University, 9160 MRB III, 465 21 Avenue South, Nashville, TN 37240, USA.
  • Reyzer ML; Mass Spectrometry Research Center, Vanderbilt University, 9160 MRB III, 465 21 Avenue South, Nashville, TN 37240, USA.
  • Caprioli RM; Mass Spectrometry Research Center, Vanderbilt University, 9160 MRB III, 465 21 Avenue South, Nashville, TN 37240, USA.
  • Hall S; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Poda S; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Sanchez PE; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Dennis MS; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Gunasekaran K; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Srivastava A; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Sandmann T; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Henne KR; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Thorne RG; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Di Paolo G; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Astarita G; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Diaz D; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Silverman AP; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Watts RJ; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Sweeney ZK; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA.
  • Kariolis MS; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA. kariolis@dnli.com henry@dnli.com.
  • Henry AG; Denali Therapeutics Inc., 161 Oyster Point Blvd., South San Francisco, CA 94080, USA. kariolis@dnli.com henry@dnli.com.
Sci Transl Med ; 12(545)2020 05 27.
Article en En | MEDLINE | ID: mdl-32461331
Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Iduronato Sulfatasa Tipo de estudio: Prognostic_studies Aspecto: Implementation_research Límite: Animals Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Iduronato Sulfatasa Tipo de estudio: Prognostic_studies Aspecto: Implementation_research Límite: Animals Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos