Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical Trials
The efficacy of adeno-associated virus (AAV)-based gene therapy is dependent on effective viral transduction, which might be inhibited by preexisting immunity to AAV acquired from infection or maternal delivery. Anti-AAV neutralizing Abs (NAbs) titer is usually measured by in vitro assay and used fo...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-03-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/16/3/400 |
| _version_ | 1797239130220920832 |
|---|---|
| author | Hanqing Wang Cengceng Zhang Zheyue Dong Xueyang Zhu Xuchu Zheng Ziyang Liu Jianfang Zhou Shuangqing Yu Xiaobing Wu Xiaoyan Dong |
| author_facet | Hanqing Wang Cengceng Zhang Zheyue Dong Xueyang Zhu Xuchu Zheng Ziyang Liu Jianfang Zhou Shuangqing Yu Xiaobing Wu Xiaoyan Dong |
| author_sort | Hanqing Wang |
| collection | DOAJ |
| description | The efficacy of adeno-associated virus (AAV)-based gene therapy is dependent on effective viral transduction, which might be inhibited by preexisting immunity to AAV acquired from infection or maternal delivery. Anti-AAV neutralizing Abs (NAbs) titer is usually measured by in vitro assay and used for patient enroll; however, this assay could not evaluate NAbs’ impacts on AAV pharmacology and potential harm in vivo. Here, we infused a mouse anti-AAV9 monoclonal antibody into Balb/C mice 2 h before receiving 1.2 × 10<sup>14</sup> or 3 × 10<sup>13</sup> vg/kg of rAAV9-coGAA by tail vein, a drug for our ongoing clinical trials for Pompe disease. The pharmacokinetics, pharmacodynamics, and cellular responses combined with in vitro NAb assay validated the different impacts of preexisting NAbs at different levels in vivo. Sustained GAA expression in the heart, liver, diaphragm, and quadriceps were observed. The presence of high-level NAb, a titer about 1:1000, accelerated vector clearance in blood and completely blocked transduction. The AAV-specific T cell responses tended to increase when the titer of NAb exceeded 1:200. A low-level NAbs, near 1:100, had no effect on transduction in the heart and liver as well as cellular responses, but decreased transduction in muscles slightly. Therefore, we propose to preclude patients with NAb titers > 1:100 from rAAV9-coGAA clinical trials. |
| first_indexed | 2024-04-24T17:46:38Z |
| format | Article |
| id | doaj.art-dabe9465ba1747fab4716797bca7c984 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-04-24T17:46:38Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-dabe9465ba1747fab4716797bca7c9842024-03-27T14:07:46ZengMDPI AGViruses1999-49152024-03-0116340010.3390/v16030400Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical TrialsHanqing Wang0Cengceng Zhang1Zheyue Dong2Xueyang Zhu3Xuchu Zheng4Ziyang Liu5Jianfang Zhou6Shuangqing Yu7Xiaobing Wu8Xiaoyan Dong9Genecradle Therapeutics Inc., Beijing 100176, ChinaGenecradle Therapeutics Inc., Beijing 100176, ChinaBeijing FivePlus Gene Technology Co., Ltd., Beijing 102629, ChinaGenecradle Therapeutics Inc., Beijing 100176, ChinaGenecradle Therapeutics Inc., Beijing 100176, ChinaGenecradle Therapeutics Inc., Beijing 100176, ChinaGenecradle Therapeutics Inc., Beijing 100176, ChinaGenecradle Therapeutics Inc., Beijing 100176, ChinaGenecradle Therapeutics Inc., Beijing 100176, ChinaGenecradle Therapeutics Inc., Beijing 100176, ChinaThe efficacy of adeno-associated virus (AAV)-based gene therapy is dependent on effective viral transduction, which might be inhibited by preexisting immunity to AAV acquired from infection or maternal delivery. Anti-AAV neutralizing Abs (NAbs) titer is usually measured by in vitro assay and used for patient enroll; however, this assay could not evaluate NAbs’ impacts on AAV pharmacology and potential harm in vivo. Here, we infused a mouse anti-AAV9 monoclonal antibody into Balb/C mice 2 h before receiving 1.2 × 10<sup>14</sup> or 3 × 10<sup>13</sup> vg/kg of rAAV9-coGAA by tail vein, a drug for our ongoing clinical trials for Pompe disease. The pharmacokinetics, pharmacodynamics, and cellular responses combined with in vitro NAb assay validated the different impacts of preexisting NAbs at different levels in vivo. Sustained GAA expression in the heart, liver, diaphragm, and quadriceps were observed. The presence of high-level NAb, a titer about 1:1000, accelerated vector clearance in blood and completely blocked transduction. The AAV-specific T cell responses tended to increase when the titer of NAb exceeded 1:200. A low-level NAbs, near 1:100, had no effect on transduction in the heart and liver as well as cellular responses, but decreased transduction in muscles slightly. Therefore, we propose to preclude patients with NAb titers > 1:100 from rAAV9-coGAA clinical trials.https://www.mdpi.com/1999-4915/16/3/400gene therapyadeno-associated viruspreexisting neutralizing antibodyPompe disease |
| spellingShingle | Hanqing Wang Cengceng Zhang Zheyue Dong Xueyang Zhu Xuchu Zheng Ziyang Liu Jianfang Zhou Shuangqing Yu Xiaobing Wu Xiaoyan Dong Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical Trials Viruses gene therapy adeno-associated virus preexisting neutralizing antibody Pompe disease |
| title | Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical Trials |
| title_full | Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical Trials |
| title_fullStr | Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical Trials |
| title_full_unstemmed | Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical Trials |
| title_short | Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical Trials |
| title_sort | using an in vivo mouse model to determine the exclusion criteria of preexisting anti aav9 neutralizing antibody titer of pompe disease patients in clinical trials |
| topic | gene therapy adeno-associated virus preexisting neutralizing antibody Pompe disease |
| url | https://www.mdpi.com/1999-4915/16/3/400 |
| work_keys_str_mv | AT hanqingwang usinganinvivomousemodeltodeterminetheexclusioncriteriaofpreexistingantiaav9neutralizingantibodytiterofpompediseasepatientsinclinicaltrials AT cengcengzhang usinganinvivomousemodeltodeterminetheexclusioncriteriaofpreexistingantiaav9neutralizingantibodytiterofpompediseasepatientsinclinicaltrials AT zheyuedong usinganinvivomousemodeltodeterminetheexclusioncriteriaofpreexistingantiaav9neutralizingantibodytiterofpompediseasepatientsinclinicaltrials AT xueyangzhu usinganinvivomousemodeltodeterminetheexclusioncriteriaofpreexistingantiaav9neutralizingantibodytiterofpompediseasepatientsinclinicaltrials AT xuchuzheng usinganinvivomousemodeltodeterminetheexclusioncriteriaofpreexistingantiaav9neutralizingantibodytiterofpompediseasepatientsinclinicaltrials AT ziyangliu usinganinvivomousemodeltodeterminetheexclusioncriteriaofpreexistingantiaav9neutralizingantibodytiterofpompediseasepatientsinclinicaltrials AT jianfangzhou usinganinvivomousemodeltodeterminetheexclusioncriteriaofpreexistingantiaav9neutralizingantibodytiterofpompediseasepatientsinclinicaltrials AT shuangqingyu usinganinvivomousemodeltodeterminetheexclusioncriteriaofpreexistingantiaav9neutralizingantibodytiterofpompediseasepatientsinclinicaltrials AT xiaobingwu usinganinvivomousemodeltodeterminetheexclusioncriteriaofpreexistingantiaav9neutralizingantibodytiterofpompediseasepatientsinclinicaltrials AT xiaoyandong usinganinvivomousemodeltodeterminetheexclusioncriteriaofpreexistingantiaav9neutralizingantibodytiterofpompediseasepatientsinclinicaltrials |