Paving the way for future gene therapies: A case study of scientific spillover from delandistrogene moxeparvovec

Asher, Damon; Dai, Daisy; Klimchak, Alexa C.; Sedita, Lauren E.; Gooch, Katherine L.; Rodino-Klapac, Louise

doi:10.1016/j.omtm.2023.08.002

Cited by 4 publications

(1 citation statement)

References 81 publications

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“…To this date, all approved AAV biologics utilize the capsids of naturally occurring AAVs 30,31 circulating in the human population, resulting in worldwide seroprevalence rates of 20-80% against different AAV serotypes 14,32 . While antibodies generated by the adaptive immune system are generally favorable to eliminate a pathogen from the host and to prevent future re-infections of the same agent, they are detrimental to the success of AAV-mediated gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing

Mietzsch,

Nelson,

Hsi

et al. 2024

Preprint

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Monoclonal antibodies (mAbs) are useful tools to dissect the neutralizing antibody response against the adeno-associated virus (AAV) capsids used as gene therapy delivery vectors. This study structurally characterizes the interactions of 21 human-derived antibodies from patients treated with the AAV9 vector, Zolgensma®, utilizing high-resolution cryo-electron microscopy. The majority of the bound antibodies do not conform to the icosahedral symmetry of the capsid, thus requiring localized reconstructions. These complex structures provide unprecedented details of the mAbs binding interfaces, with some antibodies inducing structural perturbations of the capsid upon binding. Key surface capsid amino acid residues were identified facilitating the design of capsid variants with an antibody escape phenotype, with the potential to expand the patient cohort treatable with AAV9 vectors to include those that were previously excluded due to their pre-existing neutralizing antibodies, and possibly also to those requiring redosing.

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Section: Discussionmentioning

confidence: 99%

Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing

Mietzsch,

Nelson,

Hsi

et al. 2024

Preprint

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Decoding the genetic landscape of autism: A comprehensive review

Al-Beltagi,

Saeed,

Bediwy

et al. 2024

World J Clin Pediatr

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BACKGROUND Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings. Recent advancements in genetic and epigenetic research have provided insights into the intricate mechanisms contributing to ASD, influencing both diagnosis and therapeutic strategies. AIM To explore the genetic architecture of ASD, elucidate mechanistic insights into genetic mutations, and examine gene-environment interactions. METHODS A comprehensive systematic review was conducted, integrating findings from studies on genetic variations, epigenetic mechanisms (such as DNA methylation and histone modifications), and emerging technologies [including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 and single-cell RNA sequencing]. Relevant articles were identified through systematic searches of databases such as PubMed and Google Scholar. RESULTS Genetic studies have identified numerous risk genes and mutations associated with ASD, yet many cases remain unexplained by known factors, suggesting undiscovered genetic components. Mechanistic insights into how these genetic mutations impact neural development and brain connectivity are still evolving. Epigenetic modifications, particularly DNA methylation and non-coding RNAs, also play significant roles in ASD pathogenesis. Emerging technologies like CRISPR-Cas9 and advanced bioinformatics are advancing our understanding by enabling precise genetic editing and analysis of complex genomic data. CONCLUSION Continued research into the genetic and epigenetic underpinnings of ASD is crucial for developing personalized and effective treatments. Collaborative efforts integrating multidisciplinary expertise and international collaborations are essential to address the complexity of ASD and translate genetic discoveries into clinical practice. Addressing unresolved questions and ethical considerations surrounding genetic research will pave the way for improved diagnostic tools and targeted therapies, ultimately enhancing outcomes for individuals affected by ASD.

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