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3. Safe and Sustained Expression of Human Iduronidase After Intrathecal Administration of Adeno-Associated Virus Serotype 9 in Infant Rhesus Monkeys

Author

Hordeaux, Juliette, Hinderer, Christian, Buza, Elizabeth L, Louboutin, Jean-Pierre, Jahan, Tahsin, Bell, Peter, Chichester, Jessica A, Tarantal, Alice F, and Wilson, James M

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Rare Diseases, Brain Disorders, Genetics, Mucopolysaccharidoses (MPS), Pediatric, Biotechnology, Gene Therapy, Neurosciences, 5.2 Cellular and gene therapies, Neurological, Animals, Dependovirus, Female, Ganglia, Spinal, Gene Expression, Gene Transfer Techniques, Genetic Therapy, Genetic Vectors, Humans, Iduronidase, Immunohistochemistry, Injections, Spinal, Macaca mulatta, Neurons, Organ Specificity, Promoter Regions, Genetic, Serogroup, Tissue Distribution, Transgenes, AAV9, intrathecal, MPS I, infant, rhesus monkey, Clinical Sciences, Medical biotechnology
Abstract

Many neuropathic diseases cause early, irreversible neurologic deterioration, which warrants therapeutic intervention during the first months of life. In the case of mucopolysaccharidosis type I, a recessive lysosomal storage disorder that results from a deficiency of the lysosomal enzyme α-l-iduronidase (IDUA), one of the most promising treatment approaches is to restore enzyme expression through gene therapy. Specifically, administering pantropic adeno-associated virus (AAV) encoding IDUA into the cerebrospinal fluid (CSF) via suboccipital administration has demonstrated remarkable efficacy in large animals. Preclinical safety studies conducted in adult nonhuman primates supported a positive risk-benefit profile of the procedure while highlighting potential subclinical toxicity to primary sensory neurons located in the dorsal root ganglia (DRG). This study investigated the long-term performance of intrathecal cervical AAV serotype 9 gene transfer of human IDUA administered to 1-month-old rhesus monkeys (N = 4) with half of the animals tolerized to the human transgene at birth via systemic administration of an AAV serotype 8 vector expressing human IDUA from the liver. Sustained expression of the transgene for almost 4 years is reported in all animals. Transduced cells were primarily pyramidal neurons in the cortex and hippocampus, Purkinje cells in the cerebellum, lower motor neurons, and DRG neurons. Both tolerized and non-tolerized animals were robust and maintained transgene expression as measured by immunohistochemical analysis of brain tissue. However, the presence of antibodies in the non-tolerized animals led to a loss of measurable levels of secreted enzyme in the CSF. These results support the safety and efficiency of treating neonatal rhesus monkeys with AAV serotype 9 gene therapy delivered into the CSF.

Published
2019

5. Neuropathological Findings in Nonclinical Species Following Administration of Adeno-Associated Virus (AAV)-Based Gene Therapy Vectors.

Author

Bolon, Brad, Buza, Elizabeth, Galbreath, Elizabeth, Wicks, Joan, Cargnin, Francesca, and Hordeaux, Juliette

Subjects
*PERIPHERAL nervous system, *CENTRAL nervous system, *NERVOUS system, *SENSORY ganglia, *AUTONOMIC ganglia
Abstract

Adeno-associated virus (AAV) gene therapy vectors are an accepted platform for treating severe neurological diseases. Test article (TA)-related and procedure-related neuropathological effects following administration of AAV-based vectors are observed in the central nervous system (CNS) and peripheral nervous system (PNS). Leukocyte accumulation (mononuclear cell infiltration > inflammation) may occur in brain, spinal cord, spinal nerve roots (SNRs), sensory and autonomic ganglia, and rarely nerves. Leukocyte accumulation may be associated with neuron necrosis (sensory ganglia > CNS) and/or glial changes (microgliosis and/or astrocytosis in the CNS, increased satellite glial cellularity in ganglia and/or Schwann cellularity in nerves). Axonal degeneration secondary to neuronal injury may occur in the SNR (dorsal > ventral), spinal cord (dorsal and occasionally lateral funiculi), and brainstem centrally and in nerves peripherally. Patterns of AAV-associated microscopic findings in the CNS and PNS differ for TAs administered into brain parenchyma (where tissue at the injection site is affected most) versus TAs delivered into cerebrospinal fluid (CSF) or systemically (which primarily impacts sensory ganglion neurons and their processes in SNR and spinal cord). Changes related to the TA and procedure may overlap. While often interpreted as adverse, AAV-associated neuronal necrosis and axonal degeneration of limited severity generally do not preclude clinical testing. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Agreement in Histological Assessment of Mitotic Activity Between Microscopy and Digital Whole Slide Images Informs Conversion for Clinical Diagnosis

Author

Wei, Bih-Rong, Halsey, Charles H., Hoover, Shelley B., Puri, Munish, Yang, Howard H., Gallas, Brandon D., Lee, Maxwell P., Chen, Weijie, Durham, Amy C., Dwyer, Jennifer E., Sánchez, Melissa D., Traslavina, Ryan P., Frank, Chad, Bradley, Charles, McGill, Lawrence D., Esplin, D. Glen, Schaffer, Paula A., Cramer, Sarah D., Lyle, L. Tiffany, Beck, Jessica, Buza, Elizabeth, Gong, Qi, Hewitt, Stephen M., and Simpson, R. Mark

Published
2019
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10. Automated Computational Detection, Quantitation, and Mapping of Mitosis in Whole-Slide Images for Clinically Actionable Surgical Pathology Decision Support

Author

Puri, Munish, Hoover, Shelley B., Hewitt, Stephen M., Wei, Bih-Rong, Adissu, Hibret Amare, Halsey, Charles H.C., Beck, Jessica, Bradley, Charles, Cramer, Sarah D., Durham, Amy C., Esplin, D. Glen, Frank, Chad, Lyle, L. Tiffany, McGill, Lawrence D., Sánchez, Melissa D., Schaffer, Paula A., Traslavina, Ryan P., Buza, Elizabeth, Yang, Howard H., Lee, Maxwell P., Dwyer, Jennifer E., and Simpson, R. Mark

Published
2019
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16. Scientific and Regulatory Policy Committee Points to Consider: Sampling, Processing, Evaluation, Interpretation, and Reporting of Test Article-Related Ganglion Pathology for Nonclinical Toxicity Studies

Author

Bennet, Bindu M., primary, Pardo, Ingrid D., additional, Assaf, Basel T., additional, Buza, Elizabeth, additional, Cramer, Sarah, additional, Crawford, LaTasha K., additional, Engelhardt, Jeffery A., additional, Grubor, Branka, additional, Morrison, James P., additional, Osborne, Tanasa S., additional, Sharma, Alok K., additional, and Bolon, Brad, additional

Published
2023
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21. Supplementary Figure Legends from Systematic In Vivo Inactivation of Chromatin-Regulating Enzymes Identifies Setd2 as a Potent Tumor Suppressor in Lung Adenocarcinoma

Author

Walter, David M., primary, Venancio, Olivia S., primary, Buza, Elizabeth L., primary, Tobias, John W., primary, Deshpande, Charuhas, primary, Gudiel, A. Andrea, primary, Kim-Kiselak, Caroline, primary, Cicchini, Michelle, primary, Yates, Travis J., primary, and Feldser, David M., primary

Published
2023
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22. Supplementary Table 1 from Systematic In Vivo Inactivation of Chromatin-Regulating Enzymes Identifies Setd2 as a Potent Tumor Suppressor in Lung Adenocarcinoma

Author

Walter, David M., primary, Venancio, Olivia S., primary, Buza, Elizabeth L., primary, Tobias, John W., primary, Deshpande, Charuhas, primary, Gudiel, A. Andrea, primary, Kim-Kiselak, Caroline, primary, Cicchini, Michelle, primary, Yates, Travis J., primary, and Feldser, David M., primary

Published
2023
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23. Supplementary Table 3 from Systematic In Vivo Inactivation of Chromatin-Regulating Enzymes Identifies Setd2 as a Potent Tumor Suppressor in Lung Adenocarcinoma

Author

Walter, David M., primary, Venancio, Olivia S., primary, Buza, Elizabeth L., primary, Tobias, John W., primary, Deshpande, Charuhas, primary, Gudiel, A. Andrea, primary, Kim-Kiselak, Caroline, primary, Cicchini, Michelle, primary, Yates, Travis J., primary, and Feldser, David M., primary

Published
2023
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24. Supplementary Table 2 from Systematic In Vivo Inactivation of Chromatin-Regulating Enzymes Identifies Setd2 as a Potent Tumor Suppressor in Lung Adenocarcinoma

Author

Walter, David M., primary, Venancio, Olivia S., primary, Buza, Elizabeth L., primary, Tobias, John W., primary, Deshpande, Charuhas, primary, Gudiel, A. Andrea, primary, Kim-Kiselak, Caroline, primary, Cicchini, Michelle, primary, Yates, Travis J., primary, and Feldser, David M., primary

Published
2023
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25. Supplementary Figures 1-10. from Systematic In Vivo Inactivation of Chromatin-Regulating Enzymes Identifies Setd2 as a Potent Tumor Suppressor in Lung Adenocarcinoma

Author

Walter, David M., primary, Venancio, Olivia S., primary, Buza, Elizabeth L., primary, Tobias, John W., primary, Deshpande, Charuhas, primary, Gudiel, A. Andrea, primary, Kim-Kiselak, Caroline, primary, Cicchini, Michelle, primary, Yates, Travis J., primary, and Feldser, David M., primary

Published
2023
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27. Supplementary Figure 6 from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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28. Supplementary Figure 8 from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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29. Supplementary Figure 2 from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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30. Supplementary Figure 3 from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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31. Supplementary Figure 1 from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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32. Supplementary Figure 4 from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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33. Supplementary Figure 5 from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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34. Supplementary Table 1 from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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35. Supplementary Materials and Methods from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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36. Data from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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37. Supplementary Figure Legends from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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38. Supplementary Figure 7 from Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

Author

Lo, Albert, primary, Wang, Liang-Chuan S., primary, Scholler, John, primary, Monslow, James, primary, Avery, Diana, primary, Newick, Kheng, primary, O'Brien, Shaun, primary, Evans, Rebecca A., primary, Bajor, David J., primary, Clendenin, Cynthia, primary, Durham, Amy C., primary, Buza, Elizabeth L., primary, Vonderheide, Robert H., primary, June, Carl H., primary, Albelda, Steven M., primary, and Puré, Ellen, primary

Published
2023
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39. Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase

Author

Hordeaux, Juliette, primary, Ramezani, Ali, additional, Tuske, Steve, additional, Mehta, Nickita, additional, Song, Chunjuan, additional, Lynch, Anna, additional, Lupino, Katherine, additional, Chichester, Jessica A., additional, Buza, Elizabeth L., additional, Dyer, Cecilia, additional, Yu, Hongwei, additional, Bell, Peter, additional, Weimer, Jill M., additional, Do, Hung, additional, and Wilson, James M., additional

Published
2023
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41. Scientific and Regulatory Policy Committee Technical Review: Biology and Pathology of Ganglia in Animal Species Used for Nonclinical Safety Testing.

Author

Bennet, Bindu M., Pardo, Ingrid D., Assaf, Basel T., Buza, Elizabeth, Cramer, Sarah D., Crawford, LaTasha K., Engelhardt, Jeffery A., Galbreath, Elizabeth J., Grubor, Branka, Morrison, James P., Osborne, Tanasa S., Sharma, Alok K., and Bolon, Brad

Subjects
GANGLIA, ANIMAL species, AUTONOMIC ganglia, SENSORY ganglia, CENTRAL nervous system, SPINAL nerve roots
Abstract

Dorsal root ganglia (DRG), trigeminal ganglia (TG), other sensory ganglia, and autonomic ganglia may be injured by some test article classes, including anti-neoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, nerve growth factor inhibitors, and aminoglycoside antibiotics. This article reviews ganglion anatomy, cytology, and pathology (emphasizing sensory ganglia) among common nonclinical species used in assessing product safety for such test articles (TAs). Principal histopathologic findings associated with sensory ganglion injury include neuron degeneration, necrosis, and/or loss; increased satellite glial cell and/or Schwann cell numbers; and leukocyte infiltration and/or inflammation. Secondary nerve fiber degeneration and/or glial reactions may occur in nerves, dorsal spinal nerve roots, spinal cord (dorsal and occasionally lateral funiculi), and sometimes the brainstem. Ganglion findings related to TA administration may result from TA exposure and/or trauma related to direct TA delivery into the central nervous system or ganglia. In some cases, TA-related effects may need to be differentiated from a spectrum of artifactual and/or spontaneous background changes. [ABSTRACT FROM AUTHOR]

Published
2023
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44. Efficacy and Safety of a Krabbe Disease Gene Therapy

Author

Hordeaux, Juliette, primary, Jeffrey, Brianne A., additional, Jian, Jinlong, additional, Choudhury, Gourav R., additional, Michalson, Kristofer, additional, Mitchell, Thomas W., additional, Buza, Elizabeth L., additional, Chichester, Jessica, additional, Dyer, Cecilia, additional, Bagel, Jessica, additional, Vite, Charles H., additional, Bradbury, Allison M., additional, and Wilson, James M., additional

Published
2022
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47. Engineering the gut microbiota to treat hyperammonemia

Author

Shen, Ting-Chin David, Albenberg, Lindsey, Bittinger, Kyle, Chehoud, Christel, Chen, Ying-Yu, Judge, Colleen A., Chau, Lillian, Ni, Josephine, Sheng, Michael, Lin, Andrew, Wilkins, Benjamin J., Buza, Elizabeth L., Lewis, James D., Daikhin, Yevgeny, Nissim, Ilana, Yudkoff, Marc, Bushman, Frederic D., and Wu, Gary D.

Published
2015
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49. Meganuclease targeting of PCSK9 in macaque liver leads to stable reduction in serum cholesterol.

Author

Wang, Lili, Smith, Jeff, Breton, Camilo, Clark, Peter, Zhang, Jia, Ying, Lei, Che, Yan, Lape, Janel, Bell, Peter, Calcedo, Roberto, Buza, Elizabeth L, Saveliev, Alexei, Bartsevich, Victor V, He, Zhenning, White, John, Li, Mingyao, Jantz, Derek, and Wilson, James M

Abstract

Genome editing in non-human primates with a PCSK9-targeted meganuclease lowers cholesterol levels. Clinical translation of in vivo genome editing to treat human genetic diseases requires thorough preclinical studies in relevant animal models to assess safety and efficacy. A promising approach to treat hypercholesterolemia is inactivating the secreted protein PCSK9, an antagonist of the LDL receptor. Here we show that single infusions in six non-human primates of adeno-associated virus vector expressing an engineered meganuclease targeting PCSK9 results in dose-dependent disruption of PCSK9 in liver, as well as a stable reduction in circulating PCSK9 and serum cholesterol. Animals experienced transient, asymptomatic elevations of serum transaminases owing to the formation of T cells against the transgene product. Vector DNA and meganuclease expression declined rapidly, leaving stable populations of genome-edited hepatocytes. A second-generation PCSK9-specific meganuclease showed reduced off-target cleavage. These studies demonstrate efficient, physiologically relevant in vivo editing in non-human primates, and highlight safety considerations for clinical translation. [ABSTRACT FROM AUTHOR]

Published
2022
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