Screening data from 19 patients with late-onset Pompe disease for a phase I clinical trial of AAV8 vector-mediated gene therapy
© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM..
Late-onset Pompe disease (LOPD) is a multisystem disorder with significant myopathy. The standard treatment is enzyme replacement therapy (ERT), a therapy that is lifesaving, yet with limitations. Clinical trials have emerged for other potential treatment options, including adeno-associated virus (AAV) gene therapy. We present clinical parameters and AAV antibody titers for 19 individuals with LOPD undergoing screening for a Phase I clinical trial with an AAV serotype 8 vector targeting hepatic transduction (AAV2/8-LSPhGAA). Reported clinical parameters included GAA genotype, assessments of muscle function, upright and supine spirometry, anti-recombinant human GAA antibody titers, and biomarkers. Variability in measured parameters and phenotypes of screened individuals was evident. Eligibility criteria required that all participants have six-minute walk test (6MWT) and upright forced vital capacity (FVC) below the expected range for normal individuals, and were stably treated with ERT for >2 years. All participants had Pompe disease diagnosed by enzyme deficiency, and all had the common c.-32-13T>G LOPD pathogenic variant. Screening identified 14 patients (74%) with no or minimal detectable neutralizing antibodies against AAV8 (titer ≤1:5). 6MWT distance varied significantly (percent of expected distance ranging from 24% to 91% with an average of 60 and standard deviation of 21). Upright FVC percent predicted ranged from 35% predicted to 91% predicted with an average of 66 and standard deviation of 18. None of the participants had significantly elevated alanine transaminase, which has been associated with LOPD and could complicate screening for hepatitis related to AAV gene therapy. We review the parameters considered in screening for eligibility for a clinical trial of AAV8 vector-mediated gene therapy.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:64 |
|---|---|
| Enthalten in: |
JIMD reports - 64(2023), 5 vom: 30. Sept., Seite 393-400 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Hannah, William B [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Adeno‐associated virus |
|---|
| Anmerkungen: |
Date Revised 15.09.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1002/jmd2.12391 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM361986637 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM361986637 | ||
| 003 | DE-627 | ||
| 005 | 20231226090310.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/jmd2.12391 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1206.xml |
| 035 | |a (DE-627)NLM361986637 | ||
| 035 | |a (NLM)37701327 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Hannah, William B |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Screening data from 19 patients with late-onset Pompe disease for a phase I clinical trial of AAV8 vector-mediated gene therapy |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 15.09.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM. | ||
| 520 | |a Late-onset Pompe disease (LOPD) is a multisystem disorder with significant myopathy. The standard treatment is enzyme replacement therapy (ERT), a therapy that is lifesaving, yet with limitations. Clinical trials have emerged for other potential treatment options, including adeno-associated virus (AAV) gene therapy. We present clinical parameters and AAV antibody titers for 19 individuals with LOPD undergoing screening for a Phase I clinical trial with an AAV serotype 8 vector targeting hepatic transduction (AAV2/8-LSPhGAA). Reported clinical parameters included GAA genotype, assessments of muscle function, upright and supine spirometry, anti-recombinant human GAA antibody titers, and biomarkers. Variability in measured parameters and phenotypes of screened individuals was evident. Eligibility criteria required that all participants have six-minute walk test (6MWT) and upright forced vital capacity (FVC) below the expected range for normal individuals, and were stably treated with ERT for >2 years. All participants had Pompe disease diagnosed by enzyme deficiency, and all had the common c.-32-13T>G LOPD pathogenic variant. Screening identified 14 patients (74%) with no or minimal detectable neutralizing antibodies against AAV8 (titer ≤1:5). 6MWT distance varied significantly (percent of expected distance ranging from 24% to 91% with an average of 60 and standard deviation of 21). Upright FVC percent predicted ranged from 35% predicted to 91% predicted with an average of 66 and standard deviation of 18. None of the participants had significantly elevated alanine transaminase, which has been associated with LOPD and could complicate screening for hepatitis related to AAV gene therapy. We review the parameters considered in screening for eligibility for a clinical trial of AAV8 vector-mediated gene therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Pompe disease | |
| 650 | 4 | |a adeno‐associated virus | |
| 650 | 4 | |a gene therapy | |
| 700 | 1 | |a Case, Laura E |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Edward C |e verfasserin |4 aut | |
| 700 | 1 | |a Walters, Crista |e verfasserin |4 aut | |
| 700 | 1 | |a Bali, Deeksha |e verfasserin |4 aut | |
| 700 | 1 | |a Kishnani, Priya S |e verfasserin |4 aut | |
| 700 | 1 | |a Koeberl, Dwight D |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t JIMD reports |d 2011 |g 64(2023), 5 vom: 30. Sept., Seite 393-400 |w (DE-627)NLM225225514 |x 2192-8304 |7 nnns |
| 773 | 1 | 8 | |g volume:64 |g year:2023 |g number:5 |g day:30 |g month:09 |g pages:393-400 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1002/jmd2.12391 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 64 |j 2023 |e 5 |b 30 |c 09 |h 393-400 | ||