Phase I Trial of Intramuscular Injection of a Recombinant Adeno-Associated Virus Alpha 1-Antitrypsin (rAAV2-CB-hAAT) Gene Vector to AAT-Deficient Adults

Flotte, TR; Ml, Brantly; Lt, Spencer; Byrne, Barry J.; Ct, Spencer; Dj, Baker; Humphries, Margaret

doi:10.1089/10430340460732490

Cited by 94 publications

(13 citation statements)

References 89 publications

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“…This delivery system can be achieved by using AAV vectors. Recombinant AAV vectors have been used safely in clinical trials for a number of ocular diseases such as Leber congenital amaurosis 23–25 and nonocular diseases that include hemophilia B, 26,27 cystic fibrosis, 28 α 1 -antitrypsin deficiency, 29 Parkinson disease, 30 Batten disease, 31 and muscular dystrophy. 32 The RGC layer exclusively affected in LHON can be targeted by optimizing the vector serotype, AAV2, and by choosing the route of vector administration, intravitreal injection, as we did here.…”

Section: Discussionmentioning

confidence: 99%

Safety and Effects of the Vector for the Leber Hereditary Optic Neuropathy Gene Therapy Clinical Trial

Koilkonda

Chou

et al. 2014

JAMA Ophthalmol

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IMPORTANCEWe developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene.OBJECTIVE To demonstrate the safety and effects of the gene therapy vector to be used in a proposed gene therapy clinical trial. DESIGN AND SETTINGIn a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression). The gene was packaged into adeno-associated viral vectors and then vitreally injected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration by immunohistochemical analysis and blue native polyacrylamide gel electrophoresis. During serial follow-up, the animal eyes underwent fundus photography, optical coherence tomography, and multifocal or pattern electroretinography. We tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON.EXPOSURE Ocular infection with recombinant adeno-associated viral vectors containing a wild-type allotopic human ND4 gene. MAIN OUTCOMES AND MEASURES Expression of human ND4 and rescue of optic neuropathy induced by mutant human ND4.RESULTS We found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I. In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells, and prevented demise of axons in the optic nerve. Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells. Primates undergoing vitreal injection with the ND4 test article and followed up for 3 months had no serious adverse reactions.CONCLUSIONS AND RELEVANCE Expression of our allotopic ND4 vector in the ex vivo human eye, safety of the test article, rescue of the LHON mouse model, and the severe irreversible loss of visual function in LHON support clinical testing with mutated G11778A mitochondrial DNA in our patients.

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Section: Discussionmentioning

confidence: 99%

Safety and Effects of the Vector for the Leber Hereditary Optic Neuropathy Gene Therapy Clinical Trial

Koilkonda

Chou

et al. 2014

JAMA Ophthalmol

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“…If the date of the start of the trial was not available in clinicaltrials.gov website, the date of publication of the results is mentioned. The list of trials announced for 2017 is indicative and does not pretend to be exhaustiveYear (start of trial)Viral vectorDiseaseProductTherapeuticSponsorRouteDoseNumber of treated patientsStatusReference Clinicaltrial.gov identifier1992MoMLV Retrovirus 5Homozygous familial hypercholesterolaemiaNALDL receptor geneUniversity of Michigan Ann ArbourIntraportal (Ex vivo approach)1 to 3.3 × 10e9 hepatocytes5TerminatedGrossman et al 1994 Grossman et al 1995 Raper et al 1996 NCT000048091998Adenovirus 5Ornithine transcarbamylase deficiencyNAOTC geneUniversity of PennsylvaniaIntrahepatic2 × 10e9 to 6 × 10e11vg/kg18TerminatedRaper et al 2003 NCT000044981999AAV2Haemophilia BNAFactor IX geneNAIntramuscular2 × 10e11 to 1.8 × 10e12vg/kg8TerminatedKay et al 2000 Manno et al 2003 NA2003MoMLV RetrovirusHaemophilia ANAFVIII geneChironIntravenous2.8 × 10e7 to 4.4 × 10e8vg/kg13TerminatedPowell et al 2003 NA2004HD-AdenovirusHaemophilia ANAFVIII geneGenStarIntravenous4.3 × 10e10vg/kg1TerminatedChuah et al 2004 NA2004AAV2α1-antitrypsinNAhAAtUniversity MassachussetsIntramuscular2.1 × 10e12 to 6.9 × 10e13vg12TerminatedFlotte et al 2004 Brantly et al 2006 NCT003774162004AAV2Haemophilia BNAFactor IX geneAvigenIntrahepatic8 × 10e10 to 2 × 10e...…”

Section: Clinical Successes Of Liver-directed Aav-mediated Gene Therapymentioning

confidence: 99%

“…A first trial based on an AAV2 capsid showed an acceptable safety profile with mild local reactions at the site of intramuscular injection (redness, tenderness, bruising) and a seroconversion against AAV2. Unfortunately, only one out of 12 patients demonstrated a minimal increase of plasma M α1-antitrypsin at 82 nM (Flotte et al 2004; Brantly et al 2006). Two other trials (phase I then phase II) were conducted with a vector based on AAV1 capsid known for its better muscle transduction compared to AAV2 (Flotte et al 2011).…”

Section: Considerations For Paediatric Applicationmentioning

confidence: 99%

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Baruteau

Waddington

Alexander

et al. 2017

J of Inher Metab Disea

104

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Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics.

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“…They are the focus of several phase 1/2 clinical trials involving a variety of different genetic disorders including hemophilia B, lysosomal storage disorders, inherited retinal degeneration, α-1 antitrypsin, and lipoprotein lipase deficiency. 13–18 In addition to their excellent safety profile, the most attractive attribute of these vectors is their ability to mediate persistent therapeutic transgene expression after a single administration of vector in a variety of animal models. 7,8,19–22 Emerging results from clinical trials suggest that long-term persistent expression of a transgene is indeed achievable in humans.…”

Section: Introductionmentioning

confidence: 99%

AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage

Binny

McIntosh

Peruta

et al. 2012

Blood

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We explored adeno-associated viral vector (AAV)–mediated gene transfer in the perinatal period in animal models of severe congenital factor VII (FVII) deficiency, a disease associated with early postnatal life-threatening hemorrhage. In young adult mice with plasma FVII < 1% of normal, a single tail vein administration of AAV (1 × 1013 vector genomes [vg]/kg) resulted in expression of murine FVII at 266% ± 34% of normal for ≥ 67 days, which mediated protection against fatal hemorrhage and significantly improved survival. Codon optimization of human FVII (hFVIIcoop) improved AAV transgene expression by 37-fold compared with the wild-type hFVII cDNA. In adult macaques, a single peripheral vein injection of 2 × 1011 vg/kg of the hFVIIcoop AAV vector resulted in therapeutic levels of hFVII expression that were equivalent in males (10.7% ± 3.1%) and females (12.3% ± 0.8%). In utero delivery of this vector in the third trimester to fetal monkeys conferred expression of hFVII at birth of 20.4% ± 3.7%, with a gradual decline to > 1% by 7 weeks. Re-administration of an alternative serotype at 12 months postnatal age increased hFVII levels to 165% ± 6.2% of normal, which remained at therapeutic levels for a further 28 weeks without toxicity. Thus, perinatal AAV-mediated gene transfer shows promise for disorders with onset of pathology early after birth.

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Phase I Trial of Intramuscular Injection of a Recombinant Adeno-Associated Virus Alpha 1-Antitrypsin (rAAV2-CB-hAAT) Gene Vector to AAT-Deficient Adults

Cited by 94 publications

References 89 publications

Safety and Effects of the Vector for the Leber Hereditary Optic Neuropathy Gene Therapy Clinical Trial

Safety and Effects of the Vector for the Leber Hereditary Optic Neuropathy Gene Therapy Clinical Trial

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage

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