Advances in viral vector technology: Anc-AAV & evolutionary guided vector design

Gene therapy is a potent modality with demonstrated ability to intervene in diseases of unmet medical need. Its safety and efficacy is often governed by the vector system used. Adeno-associated viral vectors (AAV) have shown great promise for sustained expression of a therapeutic gene in vivo. Obstacles remain however for gene therapy to broaden its impact beyond niche indications; currently clinically considered AAVs are repurposed naturally occurring viral entities that bring along limitations imposed by its viral biology. For example, AAVs is endemic in humans which results in a large proportion of patients to harbor memory responses to AAV antigens, preventing them to benefit from a future AAV gene therapy. Other constraints include AAV’s limited genetic cargo capacity, poor targeting of tissue targets (e.g. kidney, cochlea), and a desire to increase transduction specificity of an inherently promiscuous virus. This webinar provides insight into:

• The novel discovery efforts aimed at building synthetic AAV-based gene transfer vehicles that diverge sufficiently from their natural peers
• The challenges in retaining the superior features that have justified AAV's current clinical use
• Their work in deconstructing the putative viral evolutionary lineage of most of the commonly used AAVs using Ancestral Sequence Reconstruction
• Subsequent efforts that have led on the one hand to a set of uniquely distinct AAVs with potent transduction of therapeutically relevant tissues (including liver, retina, muscle, and cochlea). On the other hand, they actively exploit these novel reagents to deepen our structure-function understanding toward the development of improved clinical gene transfer reagents

Luk H Vandenberghe

Harvard Medical School

LUK H VANDENBERGHE, PHD, is an Assistant Professor at
Harvard Medical School and Associate Member of the Broad Institute of
Harvard and MIT in Boston, MA, USA. He directs the Grousbeck Gene
Therapy Center at Massachusetts Eye and Ear Infirmary in Boston, USA,
a part of the Ocular Genomics Institute, a bench to bedside research
program to study, diagnose, and develop treatments for diseases of the
eye. His previous work led to the discovery of novel AAV serotypes such
as AAV9, novel insights into AAV structure-function, and vector immunobiology.
His laboratory at Harvard addresses mechanistic questions on
AAV virology, develops technologies aiming to overcome hurdles to gene
therapy clinical applications, and actively translates gene therapy programs
in hearing and vision. His research focuses on delivery questions,
specifically on the adeno-associated virus (AAV) for therapeutic gene delivery.
Recent studies leverage structural and evolutionary information
on AAV as a starting point for the design of synthetic viral vector systems,
a first generation of which is referred to as AncAAVs which are now
progressing to the clinic for a number of indications. Dr. Vandenberghe
previously co-founded GenSight Biologics and Akouos. He also is a
founder, board member, and advisor to Odylia Therapeutics, a non-profit
catalyzing translation for gene therapies within the challenging field of
ultra-rare disorders. Dr. Vandenberghe has over 50 peer reviewed publications
and more than a dozen licensed patents, mostly related to gene
therapy methods, technologies, and applications.

Dirk Grimm

Professor for Viral Vector Technologies at

Dirk Grimm, PhD is Full Professor for Viral Vector Technologies at Heidelberg University Hospital. He was trained as a biologist at the Universities of Kaiserslautern and Heidelberg (Germany) and pursued a PhD in Biology with a focus on Adeno-associated viral (AAV) vector technology. His laboratory is interested in engineering novel capsid and genome variants of AAV that are specifically optimized for tissue-specific expression of elements for therapeutic gene regulation and genome editing. Dr. Grimm is a co-author on over 70 peer-reviewed publications including in Nature, Nature Structural and Molecular Biology, Journal of Clinical Investigation, Blood and other high-impact journals.

SPEAKERS

Luk H Vandenberghe

Harvard Medical School

Dirk Grimm

Professor for Viral Vector Technologies at

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