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Review
. 2021 Feb 3;29(2):464-488.
doi: 10.1016/j.ymthe.2020.12.007. Epub 2020 Dec 10.

Current Clinical Applications of In Vivo Gene Therapy with AAVs

Jerry R Mendell  1 , Samiah A Al-Zaidy  2 , Louise R Rodino-Klapac  3 , Kimberly Goodspeed  4 , Steven J Gray  4 , Christine N Kay  5 , Sanford L Boye  6 , Shannon E Boye  7 , Lindsey A George  8 , Stephanie Salabarria  9 , Manuela Corti  10 , Barry J Byrne  10 , Jacques P Tremblay  11
Affiliations
Review

Current Clinical Applications of In Vivo Gene Therapy with AAVs

Jerry R Mendell et al. Mol Ther. .

Abstract

Hereditary diseases are caused by mutations in genes, and more than 7,000 rare diseases affect over 30 million Americans. For more than 30 years, hundreds of researchers have maintained that genetic modifications would provide effective treatments for many inherited human diseases, offering durable and possibly curative clinical benefit with a single treatment. This review is limited to gene therapy using adeno-associated virus (AAV) because the gene delivered by this vector does not integrate into the patient genome and has a low immunogenicity. There are now five treatments approved for commercialization and currently available, i.e., Luxturna, Zolgensma, the two chimeric antigen receptor T cell (CAR-T) therapies (Yescarta and Kymriah), and Strimvelis (the gammaretrovirus approved for adenosine deaminase-severe combined immunodeficiency [ADA-SCID] in Europe). Dozens of other treatments are under clinical trials. The review article presents a broad overview of the field of therapy by in vivo gene transfer. We review gene therapy for neuromuscular disorders (spinal muscular atrophy [SMA]; Duchenne muscular dystrophy [DMD]; X-linked myotubular myopathy [XLMTM]; and diseases of the central nervous system, including Alzheimer's disease, Parkinson's disease, Canavan disease, aromatic l-amino acid decarboxylase [AADC] deficiency, and giant axonal neuropathy), ocular disorders (Leber congenital amaurosis, age-related macular degeneration [AMD], choroideremia, achromatopsia, retinitis pigmentosa, and X-linked retinoschisis), the bleeding disorder hemophilia, and lysosomal storage disorders.

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Conflict of interest statement

I received consulting fees for AveXis, Amicus, Neurogene, Affinia Therapeutics, and Novartis. S.J.G. has received royalty and/or consulting income from Asklepios Biopharma, Neurogene, Abeona Therapeutics, Sarepta Therapeutics, Vertex Pharmaceuticals, LYSOGENE, and Amicus Therapeutics. L.A.G. holds intellectual property related to the use of a factor VIII variant protein for gene therapy, has served as a consultant for Pfizer, and is the clinical principal investigator for ongoing hemophilia A and B phase I/II trials sponsored by Spark Therapeutics/Roche and Pfizer, respectively.

Figures

None
Graphical abstract
Figure 1
Figure 1
Maximum Longitudinal CHOP-INTEND Scores Reached for AVXS-101 Treated with the Therapeutic Dose Compared to the Prospective Natural History (NN101) Cohort Mean CHOP-INTEND scores by infant age are shown; shaded areas indicate the standard deviation for each mean at each study visit. (Reprinted from Journal of Neuromuscular Diseaseshttps://dx.doi.org/10.3233/JND-190403.
Figure 2
Figure 2
SMA Infants Recognized from Ohio Newborn Screening Receiving Gene Therapy Prior to Onset of Symptoms with High CHOP-INTEND Scores at Baseline Continued to Improve over Time Published in Pediatrics.
See this image and copyright information in PMC

References

    1. Burghes A.H., Beattie C.E. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat. Rev. Neurosci. 2009;10:597–609. - PMC - PubMed
    1. Verhaart I.E.C., Robertson A., Wilson I.J., Aartsma-Rus A., Cameron S., Jones C.C., Cook S.F., Lochmüller H. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J. Rare Dis. 2017;12:124. - PMC - PubMed
    1. Sugarman E.A., Nagan N., Zhu H., Akmaev V.R., Zhou Z., Rohlfs E.M., Flynn K., Hendrickson B.C., Scholl T., Sirko-Osadsa D.A., Allitto B.A. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur. J. Hum. Genet. 2012;20:27–32. - PMC - PubMed
    1. Lefebvre S., Bürglen L., Reboullet S., Clermont O., Burlet P., Viollet L., Benichou B., Cruaud C., Millasseau P., Zeviani M. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80:155–165. - PubMed
    1. Monani U.R., Lorson C.L., Parsons D.W., Prior T.W., Androphy E.J., Burghes A.H., McPherson J.D. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum. Mol. Genet. 1999;8:1177–1183. - PubMed

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