Advances in CRISPR/Cas gene therapy for inborn errors of immunity

Abstract

Inborn errors of immunity (IEIs) are a group of inherited disorders caused by mutations in the protein-coding genes involved in innate and/or adaptive immunity. Hematopoietic stem cell transplantation (HSCT) is a mainstay definitive therapy for many severe IEIs. However, the lack of HLA-matched donors increases the risk of developing severe immunological complications. Gene therapy provides long-term clinical benefits and could be an attractive therapeutic strategy for IEIs. In this review, we describe the development and evolution of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas) gene-editing systems, including double-strand break (DSB)-based gene editing and DSB-free base editing or prime editing systems. Here, we discuss the advances in and issues associated with CRISPR/Cas gene editing tools and their potential as therapeutic alternatives for IEIs. We also highlight the progress of preclinical studies for the treatment of human genetic diseases, including IEIs, using CRISR/Cas and ongoing clinical trials based on this versatile technology.

Treg in inborn errors of immunity: gaps, knowns and future perspectives

“…Also, there is a variety of treatment options for the management of immune dysregulation in IEIs depending on the specific type, severity, and pathway involved in the disorder. These include systemic immunosuppressants, enzyme replacement therapy, small molecules, biological therapies (such as monoclonal antibodies), and adoptive cell therapies (ACT) such as hematopoietic stem cell transplantation (HSCT), gene therapy ( 54 , 118 , 119 ) and, in the near future, cell-based therapies. The aim of this review is to ascertain available Treg cell-based therapies more comprehensively and, as such, the other therapies will be briefly summarized.…”

“…This strategy entails the modification of HSC and other immune cells involved in the disease process. Subsequent to its inception, significant advances have been made such as using self-inactivating lentiviruses, rendering this approach a promising and safer alternative compared to its earlier iterations ( 119 , 120 ). Indeed, in 2016, Strimvelis™ was approved in Europe for the treatment for ADA-SCID.…”

“…This process employs engineered nucleases, with three primary types being utilized: Zinc-Finger Nucleases (ZFNs), Transcription activator-like effector nucleases (TALENs), and CRISPR/Cas. These molecular tools enable researchers to precisely edit the genetic material, offering a more targeted and efficient approach to treating genetic-based immune disorders ( 119 ). This technique is still in preclinical phases but demonstrates remarkable promise.…”

CRISPR-Cas: ‘The Multipurpose Molecular Tool’ for Gene Therapy and Diagnosis

“…Further human trials involving CRISPR are currently underway, with the tool having shown particular promise in the treatment of numerous conditions, including certain cancers. However, this research is the first published that involves CRISPR’s use directly inside the body [ 33 ]; almost all of the other studies performed genome editing in extracted cells, which were then reintroduced. A treatment for restoring sight by injecting CRISPR into a patient’s eye has also emerged, but it has not yet been the subject of any scientific publication.…”

“…Here, English and New Zealand teams, in association with the Intellia Therapeutics and Regeneron Pharmaceuticals laboratories, directly injected CRISPR into the blood of people suffering from transthyretin amyloidosis, an inherited disease characterized by attacks on the nervous system, kidneys, and heart. This rare pathology is characterized by a mutation in the TTR gene, which leads to the accumulation of transthyretin proteins in deposits around nerves and organs [ 31 , 33 ].…”