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Genes
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Gene Therapy for Childhood Diseases
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Gene Therapy for Childhood Diseases

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 July 2024) | Viewed by 1680

Special Issue Editor

Dr. Alisha M. Gruntman

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Guest Editor
Pediatrics, Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA
Interests: gene therapy; AAV; pulmonology; animal models; large animal models; translational gene therapy

Special Issue Information

Dear Colleagues,

With new approaches to gene therapy for childhood diseases expanding at an astounding rate and making their way to clinics, including relatively new therapeutic modalities, such as gene editing, making there way to the clinics we want to highlight some of the original research going into translational programs for a variety of diseases that affect children worldwide.

We realize that obtaining a gene therapy product approved for clinical use requires many steps from the bench to the bedside stage. We invite manuscripts that explore the transition of animal models through to clinical trials.

Dr. Alisha M. Gruntman
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • rare diseases
  • gene therapy
  • gene editing
  • animal models
  • government approval
  • neonatal testing
  • neonatal delivery
  • patient screening
  • patient recruitment

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Published Papers (1 paper)

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Research

17 pages, 2484 KiB  
Article
Limb Perfusion Delivery of a rAAV1 Alpha-1 Antitrypsin Vector in Non-Human Primates Is Safe but Insufficient for Therapy
by Debora Pires-Ferreira, Darcy Reil, Qiushi Tang, Meghan Blackwood, Thomas Gallagher, Allison M. Keeler, Jessica A. Chichester, Kristin K. Vyhnal, Jane A. Lindborg, Janet Benson, Dongtao Fu, Terence R. Flotte and Alisha M. Gruntman
Genes 2024, 15(9), 1188; https://doi.org/10.3390/genes15091188 - 10 Sep 2024
Viewed by 1356
Abstract
Background/Objectives: α-1 antitrypsin (AAT) deficiency is an inherited, genetic condition characterized by reduced serum levels of AAT and increased risk of developing emphysema and liver disease. AAT is normally synthesized primarily in the liver, but muscle-targeting with a recombinant adeno-associated virus (rAAV) vector [...] Read more.
Background/Objectives: α-1 antitrypsin (AAT) deficiency is an inherited, genetic condition characterized by reduced serum levels of AAT and increased risk of developing emphysema and liver disease. AAT is normally synthesized primarily in the liver, but muscle-targeting with a recombinant adeno-associated virus (rAAV) vector for α-1 antitrypsin (AAT) gene therapy has been used to minimize liver exposure to the virus and hepatotoxicity. Clinical trials of direct intramuscular (IM) administration of rAAV1-hAAT have demonstrated its overall safety and transgene expression for 5 years. However, the failure to reach the therapeutic target level after 100 large-volume (1.5 mL) IM injections of maximally concentrated vector led us to pursue a muscle-targeting approach using isolated limb perfusion. This targets the rAAV to a greater muscle mass and allows for a higher total volume (and thereby a higher dose) than is tolerable by multiple direct IM injections. Limb perfusion has been shown to be feasible in non-human primates using the rAAV1 serotype and a ubiquitous promoter expressing an epitope-tagged AAT matched to the host species. Methods: In this study, we performed a biodistribution and preclinical safety study in non-human primates with a clinical candidate rAAV1-human AAT (hAAT) vector at doses ranging from 3.0 × 1012 to 1.3 × 1013 vg/kg, bracketing those used in our clinical trials. Results: We found that limb perfusion delivery of rAAV1-hAAT was safe and showed a biodistribution pattern similar to previous studies. However, serum levels of AAT obtained with high-dose limb perfusion still reached only ~50% of the target serum levels. Conclusions: Our results suggest that clinically effective AAT gene therapy may ultimately require delivery at doses between 3.5 × 1013–1 × 1014 vg/kg, which is within the dose range used for approved rAAV gene therapies. Muscle-targeting strategies could be incorporated when delivering systemic administration of high-dose rAAV gene therapies to increase transduction of muscle tissues and reduce the burden on the liver, especially in diseases that can present with hepatotoxicity such as AAT deficiency. Full article
(This article belongs to the Special Issue Gene Therapy for Childhood Diseases)
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