Gene therapy for primary immunodeficiency

Booth, Claire; Gaspar, HB; Thrasher, Adrian J.

doi:10.1097/mop.0b013e32834cd67a

Cited by 32 publications

(12 citation statements)

References 46 publications

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“…The risk of insertional mutagenesis in slowly turning over differentiated lung epithelium is unknown, but is likely to be lower than in rapidly dividing bone marrow cells. In addition, the improved design of self-inactivating lentiviral vectors has improved safety (21). Here we compared survival, weight, and lung histology during a 24-month study period and did not see any differences between F/HN-SIV-and PBS-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Assessment of F/HN-Pseudotyped Lentivirus as a Clinically Relevant Vector for Lung Gene Therapy

Griesenbach

Inoue

Meng

et al. 2012

Am J Respir Crit Care Med

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Section: Discussionmentioning

confidence: 99%

Assessment of F/HN-Pseudotyped Lentivirus as a Clinically Relevant Vector for Lung Gene Therapy

Griesenbach

Inoue

Meng

et al. 2012

Am J Respir Crit Care Med

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“…25 Unfortunately, inherent risk proved unacceptably high, with mutagenic events detected for SCID-X1, 26 Wiskott-Aldrich syndrome, 27 and XCGD. 28 With a shift toward safer lentiviral vectors designed to self-inactivate, similar adverse events have yet to be observed.…”

Section: Discussionmentioning

confidence: 99%

Application of Droplet Digital PCR for Estimating Vector Copy Number States in Stem Cell Gene Therapy

Lin

Okumura

Yatsuda³

et al. 2016

Human Gene Therapy Methods

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Stable gene transfer into target cell populations via integrating viral vectors is widely used in stem cell gene therapy (SCGT). Accurate vector copy number (VCN) estimation has become increasingly important. However, existing methods of estimation such as real-time quantitative PCR are more restricted in practicality, especially during clinical trials, given the limited availability of sample materials from patients. This study demonstrates the application of an emerging technology called droplet digital PCR (ddPCR) in estimating VCN states in the context of SCGT. Induced pluripotent stem cells (iPSCs) derived from a patient with X-linked chronic granulomatous disease were used as clonable target cells for transduction with alpharetroviral vectors harboring codon-optimized CYBB cDNA. Precise primer–probe design followed by multiplex analysis conferred assay specificity. Accurate estimation of per-cell VCN values was possible without reliance on a reference standard curve. Sensitivity was high and the dynamic range of detection was wide. Assay reliability was validated by observation of consistent, reproducible, and distinct VCN clustering patterns for clones of transduced iPSCs with varying numbers of transgene copies. Taken together, use of ddPCR appears to offer a practical and robust approach to VCN estimation with a wide range of clinical and research applications.

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“…Studies using retroviral gene therapy for X-linked severe combined immunodeficiency patients have found that many patients treated with this retroviral vector developed leukemia [34]. However, newer studies offer more encouraging news: with increased experience and modified conditioning regimens, improved outcomes have been observed without oncogenetic risks after more than a 4-year follow-up of additional immune deficient patients treated with a different retrovirus vector [35]. …”

Section: Factor (F) VIII Biology: Intracellular Processing and Expresmentioning

confidence: 99%

Ectopic platelet-delivered factor (F) VIII for the treatment of Hemophilia A: Plasma and platelet FVIII, is it all the same?

Greene¹,

Lambert²,

Poncz³

2012

J Genet Syndr Gene Ther

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Hemophilia A is the most common inherited bleeding diathesis and is due to a deficiency of functional coagulation factor (F) VIII. Most patients have a severe deficiency and require a program of prophylactic plus acute infusions of recombinant FVIII to prevent significant joint and other target organ damage. One of the greatest challenges remaining in the care of these patients is that one fifth to third of the patients develop inhibitors to the infused proteins. While a significant portion of such inhibitors can be either overcome or the inhibitors eliminated, some patients with persistent and significant titers of inhibitors need to rely on second tier therapies that are not as effective at preventing significant bleeding morbidity or mortality. A number of groups have been developing therapeutic strategies for FVIII gene therapy for this disorder. Virtually all of these therapies have in common a rise in the plasma level of FVIII, and interpretation of their efficacy is straightforward related to levels achieved. However, several groups have also shown that FVIII can be ectopically expressed in developing megakaryocytes, where although plasma FVIII levels remain undetectable, this FVIII can be released and be effective at sites of platelet activation. Moreover, it is clear that this platelet (p) FVIII is protected to a degree from inhibitors, making pFVIII a particularly attractive strategy for gene therapy for hemophilia A. Yet at the same time, we have shown that pFVIII has a different availability and distribution in a growing thrombus than plasma FVIII. The clinical implications and challenges of these findings as murine and canine hemophilia A preclinical studies go forward with pFVIII are discussed.

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Gene therapy for primary immunodeficiency

Cited by 32 publications

References 46 publications

Assessment of F/HN-Pseudotyped Lentivirus as a Clinically Relevant Vector for Lung Gene Therapy

Assessment of F/HN-Pseudotyped Lentivirus as a Clinically Relevant Vector for Lung Gene Therapy

Application of Droplet Digital PCR for Estimating Vector Copy Number States in Stem Cell Gene Therapy

Ectopic platelet-delivered factor (F) VIII for the treatment of Hemophilia A: Plasma and platelet FVIII, is it all the same?

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