Advances in gene therapy for inborn errors of immunity

Abstract

Purpose of review: Provide an overview of the landmark accomplishments and state of the art of gene therapy for inborn errors of immunity (IEI).

Recent findings: Three decades after the first clinical application of gene therapy for IEI, there is one market authorized product available, while for several others efficacy has been demonstrated or is currently being tested in ongoing clinical trials. Gene editing approaches using programmable nucleases are being explored preclinically and could be beneficial for genes requiring tightly regulated expression, gain-of-function mutations and dominant-negative mutations.

Summary: Gene therapy by modifying autologous hematopoietic stem cells (HSCs) offers an attractive alternative to allogeneic hematopoietic stem cell transplantation (HSCT), the current standard of care to treat severe IEI. This approach does not require availability of a suitable allogeneic donor and eliminates the risk of graft versus host disease (GvHD). Gene therapy can be attempted by using a viral vector to add a copy of the therapeutic gene (viral gene addition) or by using programmable nucleases (gene editing) to precisely correct mutations, disrupt a gene or introduce an entire copy of a gene at a specific locus. However, gene therapy comes with its own challenges such as safety, therapeutic effectiveness and access. For viral gene addition, a major safety concern is vector-related insertional mutagenesis, although this has been greatly reduced with the introduction of safer vectors. For gene editing, the risk of off-site mutagenesis is a main driver behind the ongoing search for modified nucleases. For both approaches, HSCs have to be manipulated ex vivo, and doing this efficiently without losing stemness remains a challenge, especially for gene editing.

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FIGURE 1

Different approaches to gene therapy for IEI. In all types of gene therapy for IEI, ex vivo gene therapy is used, in which a viral vector is used to genetically modify cells from the patients with therapeutic intend. Cells could include T cells, HSCs or other cell types. For gene addition (left), gRV or LV vectors are used to add the therapeutic gene to the genome of the target cells. This occurs semi-randomly, with slight preferences for integration sites depending on the vector used. For gene editing, a specific site can be targeted to change the DNA and correct the mutation. This can be accomplished by using an engineered nuclease such as CRISPR/Cas to introduce a single or double stranded DNA break in combination with a repair template. This strategy can be used to add a full cDNA in the same gene under control of the endogenous regulatory elements. Alternatively, it can be used to add a full cDNA including regulatory elements into a known safe region of the genome elsewhere (safe harbor). This targeted approach avoids insertional mutagenesis, but allows gene expression to be controlled by design. gRV, gamma-retroviruses; HSC, hematopoietic stem cell; IEI, inborn errors of immunity; LV, lentiviral.