Genome Editing in Gene Therapy - FDA Draft Guidance for IND

With this draft, published in March 2022, the FDA wants to provide those working on the development of gene therapy products produced by genome editing with recommendations that are relevant for submitting an application for an Investigational New Drug (IND). This revolves around information that the agency requires, such as product design, product manufacturing, product testing, preclinical safety assessment and clinical trial design, which are key to the safety and quality of such a gene editing product.


The term gene editing (GE - also genome editing) refers to a whole range of new molecular biological methods with which targeted mutations or alterations are induced in very specific sections of the DNA. Genes can thus be switched on or off, inserted or removed. This also includes the well-known procedure of the gene scissors CRISPR/Cas.

The various possibilities that have been developed here in the last 10 years have enormously increased interest in the possibilities of using such technologies to treat human diseases. Since then, a whole range of gene therapy products have been developed that are based on gene technologies. There is no longer any doubt about the potential of such products in the treatment of human diseases, but the potential risks are often not so well known or researched.


This draft guideline is intended to support the transition of these products from research to clinical trials. It contains recommendations for assessing the safety and quality as well as for dealing with the potential risks of these products. Regarding the products covered by this guidance, FDA says: "For the purpose of this guidance, human GE is a process by which DNA sequences are added, deleted, altered or replaced at specified location(s) in the genome of human somatic cells, ex vivo or in vivo, using nuclease-dependent or nuclease-independent GE technologies."

The FDA believes that such human GE products must be considered and evaluated using a science-based approach. This must include an evaluation of the benefits and risks of each product to establish a benefit-risk profile. This must of course be evaluated in the context of the proposed indication and patient population, the magnitude and duration of therapeutic benefit achieved, and the availability of alternative therapeutic options.

Off-target editing in particular, an unintended consequence of on-target and off-target editing would be a specific risk of such technologies. In gene scissors methods, the guide RNA (gRNA) guides the cutting protein Cas9 to the target. This is a specific DNA sequence that is to be cut and "rewritten".

Sometimes, however, the gRNA binds at a site that is very similar to the target DNA sequence, so that Cas9 cuts the DNA there. This then leads to undesired mutations. These effects are called off-target effects (effects outside the desired target sequence). Such an effect can be influenced, for example, by the type and length of the target sequence. The longer the target sequence - and the matching guide RNA - and the fewer similarities it has with other DNA segments, the less likely off-target effects are to occur.

The document now published details the FDA's current thinking on developing human GE products for clinical trials and approval. With further developments in GE technologies and products based on them, these recommendations will be revised and adapted.

Further detail can be found directly in the draft guidance document "Human Gene Therapy Products Incorporating Human Genome Editing".

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