In vivo LNP-CRISPR Approaches for the Treatment of Hemophilia

Lee, Jeong Hyeon; Han, Jeong Pil

doi:10.1007/s40291-024-00705-1

Cited by 3 publications

(1 citation statement)

References 96 publications

(121 reference statements)

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“…In vivo technologies look especially promising, as their application can be envisioned beyond the mere deployment of the CAR components. Both viral and non-viral vectors are being actively tested for in vivo CRISPR delivery and editing ( 210 – 212 ), for oncological as well as for gene therapy applications. Even more interestingly, in vivo targeting can be envisioned for the modification of other components of TME ( 213 ), such as macrophages, regulatory cells and the cancer cells themselves, thus manipulating the cytokine, immune checkpoints and metabolite milieu.…”

Section: Perspective: Engineering a New Generation Of Safer And More ...mentioning

confidence: 99%

Engineering strategies to safely drive CAR T-cells into the future

Rossi,

Breman

2024

Front. Immunol.

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Chimeric antigen receptor (CAR) T-cell therapy has proven a breakthrough in cancer treatment in the last decade, giving unprecedented results against hematological malignancies. All approved CAR T-cell products, as well as many being assessed in clinical trials, are generated using viral vectors to deploy the exogenous genetic material into T-cells. Viral vectors have a long-standing clinical history in gene delivery, and thus underwent iterations of optimization to improve their efficiency and safety. Nonetheless, their capacity to integrate semi-randomly into the host genome makes them potentially oncogenic via insertional mutagenesis and dysregulation of key cellular genes. Secondary cancers following CAR T-cell administration appear to be a rare adverse event. However several cases documented in the last few years put the spotlight on this issue, which might have been underestimated so far, given the relatively recent deployment of CAR T-cell therapies. Furthermore, the initial successes obtained in hematological malignancies have not yet been replicated in solid tumors. It is now clear that further enhancements are needed to allow CAR T-cells to increase long-term persistence, overcome exhaustion and cope with the immunosuppressive tumor microenvironment. To this aim, a variety of genomic engineering strategies are under evaluation, most relying on CRISPR/Cas9 or other gene editing technologies. These approaches are liable to introduce unintended, irreversible genomic alterations in the product cells. In the first part of this review, we will discuss the viral and non-viral approaches used for the generation of CAR T-cells, whereas in the second part we will focus on gene editing and non-gene editing T-cell engineering, with particular regard to advantages, limitations, and safety. Finally, we will critically analyze the different gene deployment and genomic engineering combinations, delineating strategies with a superior safety profile for the production of next-generation CAR T-cell.

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Section: Perspective: Engineering a New Generation Of Safer And More ...mentioning

confidence: 99%

Engineering strategies to safely drive CAR T-cells into the future

Rossi,

Breman

2024

Front. Immunol.

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Drug‐induced liver injury related to gene therapy: A new challenge to be managed

Larrey,

Delire,

Meunier

et al. 2024

Liver International

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Gene therapy is being successfully developed for the treatment of several genetic disorders. Various methods of gene transfer have been developed to enable the production of the deficient enzyme or protein. One of the most important is adeno‐associated virus vectors, which have been shown to be viable for use in in vivo gene therapy. Several gene therapies have already been approved. They are also promising for acquired diseases. Important examples include gene therapy for haemophilia A and B, X‐linked myotubular myopathy, spinal muscular atrophy and several liver diseases such as Criggler‐Najjar disease, alpha‐1 antitrypsin deficiency and Fabry disease. However, the introduction of a foreign compound into hepatocytes leads to hepatic reactions with heterogeneous phenotypic expression and a wide spectrum of severity, ranging from mild transaminase elevation to acute liver failure. Several mechanisms appear to be involved in liver injury, including an immune response, but also direct toxicity depending on the method of gene transfer. As a result, the incidence, expression and severity of liver injury vary from indication to indication and from patient to patient. Patients treated for haemophilia A are more prone to transaminase elevation than those treated for haemophilia B. Corticosteroids are successfully used to correct liver reactions but also to prevent degradation of the transferred gene and loss of therapeutic activity. The aim of this review is to describe the risk of liver injury according to the indication for gene therapy and the short‐ and long‐term management currently proposed to prevent or correct liver reactions in clinical practice.

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The future of complement therapeutics

Kolev,

Rao,

Yeh

et al. 2024

Explor Immunol

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Complement is both evolutionary and scientifically old. It predates the adaptive immunity by some 600 million years and was first described in 1905 by Jules Bordet and Paul Ehrlich. For the most of its, the existence complement system has been ignored by most scientists and clinicians due to the perception of it being complicated and its relevance for the pathogenesis of human disease being unclear. With the recent US Food and Drug Administration (FDA) approvals of pegcetacoplan for both paroxysmal nocturnal haemoglobinuria (PNH) and geographic atrophy (GA), avacincaptad pegol for GA and iptacopan and danicopan for PNH, we are at a crucial juncture for complement-targeting therapies. A number of companies and academic institutions are developing next-generation complement therapies, which is resulting in an increasingly competitive landscape. If one looks at the serum complement cascade, all 3 pathways now have biotechnology or pharmaceutical industry players with 1 or multiple clinical-stage inhibitors that are expected to be FDA approved within the next few years. Furthermore, with the limited number of clinically validated targets in complement-mediated disease, the competition in this space is set to further intensify in the coming years. In this review, we will discuss the timeline of the academic discoveries that led to the development of the current crop of FDA-approved complement therapeutics. We follow with a discussion of an increasingly crowded complement therapy space and of the scientific advances that have emerged in recent two decades underpinning future innovation, including advances in our understanding of complement biology, such as local and intracellular complement, emerging complement targets, combinational approaches of complement and non-complement therapeutics to unlock new disease indications and new technologies such as gene therapy. We will also give a comprehensive overview of the gene therapy landscape and how it can be utilized to target complement dysregulation.

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In vivo LNP-CRISPR Approaches for the Treatment of Hemophilia

Cited by 3 publications

References 96 publications

Engineering strategies to safely drive CAR T-cells into the future

Engineering strategies to safely drive CAR T-cells into the future

Drug‐induced liver injury related to gene therapy: A new challenge to be managed

The future of complement therapeutics

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