Gene-editing therapy to treat hereditary disorder

A single treatment using a breakthrough gene-editing therapy has transformed the lives of a group of people who were suffering from a debilitating hereditary disorder. The successful treatment using the CRISPR/Cas9 gene-editing mechanism offers hope for patients diagnosed with the same condition, as well as raises the possibility of leveraging similar techniques to provide treatments for other genetic disorders.

A genetic disorder is a health problem caused by one or more abnormalities in the genome — the entire genetic information of an organism that is encoded in the DNA in the form of nucleotide sequences. To clarify this further, the nucleotide is the basic building block of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), and consists of a 5-carbon sugar molecule (either ribose in RNA or deoxyribose in DNA) attached to a phosphate group and a nitrogen-containing base. The sequence of nucleotides results in protein-coding genes, non-coding genes, and other functional regions in the genome.

Genetic disorders can arise due to a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. The mutation responsible can occur spontaneously before embryonic development (a de novo mutation), or it can be inherited from either of the parents with a disorder, or from both parents who are carriers of a faulty gene. When the genetic disorder is inherited from one or both parents, it is also referred to as a hereditary disease.

Researchers from the University of Auckland, Amsterdam University Medical Center and Cambridge University, from New Zealand, the Netherlands and the United Kingdom respectively, used the cutting-edge CRISPR/Cas9 therapy to treat ten patients from across the three countries involved. All the patients participating in the study suffered from ‘hereditary angioedema’ (HAE), a rare but serious problem with the immune system.

HAE is an inherited genetic disorder characterized by severe, painful and unpredictable rapid swelling under the skin of the hands, feet, limbs, face, intestinal tract, larynx (voicebox), or trachea (windpipe). The sudden swelling that erupts can not only interfere with daily life, but can also prove fatal if the condition affects the body’s breathing pathway. Globally, it is estimated one in 50,000 people have hereditary angioedema, however, because it is rare, it is often incorrectly diagnosed, and many patients end up receiving unnecessary treatments and invasive procedures.

HAE is caused by deficiency or improper function of the protein prekallikrein (PK). Deficiency in PK is caused by mutations in the nucleotide sequence that encodes for the KLKB1 gene, which provides the instructions for making prekallikrein. In its activated form in the blood, PK is known as plasma kallikrein, which plays a key role in a process called the intrinsic coagulation pathway, which in turn activates proteins that are needed later in the clotting process.

The KLKB1 gene mutations that cause prekallikrein deficiency reduce or eliminate functional plasma kallikrein, which has been identified with triggering acute attacks of HAE. The new gene-editing therapy, called NTLA-2002, utilizes in vivo CRISPR/Cas9 technology to target the nucleotide sequence that encodes for the KLKB1 gene. By editing this gene, the therapy improves the production of plasma kallikrein, effectively preventing angioedema (swelling) attacks.

So far, the only approved CRISPR therapy, CASGEVY, used for treating sickle cell disease and beta thalassemia, is an ex vivo CRISPR therapy, where the cells are taken from the patient and edited outside of the body and then reinfused. In contrast, NTLA-2002 uses in vivo CRISPR therapy, where the targeted gene editing occurs directly within the body. The NTLA-2002 therapy is among the first successful uses of in vivo CRISPR therapy.

Clustered regularly interspaced short palindromic repeats, or CRISPR/Cas9 for short, have transformed genome engineering techniques in recent years, and is poised to not only enable doctors to treat patients but also prevent many diseases. Basically, CRISPR technology involves targeting a specific section of DNA inside a cell that is causing a health problem. The technology has also been adapted to perform other functions, including turning genes on or off without altering their sequence. CRISPR technologies are now increasingly being used to develop treatment for a wide range of diseases, such as genetic disease, cardiovascular disease, cancer and autoimmune diseases.

An interim report on phase one of the NTLA-2002 therapy published recently noted that a single-dose treatment was found to provide a permanent cure for the participating hereditary angioedema patients. Based on the dose administered, the treatment was found to achieve on average up to 95 percent improvement in total plasma kallikrein protein. The study also showed the potential to develop similar CRISPR/Cas9 treatments for other genetic disorders. The report on the phase one study also noted that there were no serious or lasting side-effects from the single infusion, which took place over two to four hours under clinical supervision.

The patients from the initial study will now be under observation and follow-up for the next 15 years to continue assessing long-term safety and efficacy of the treatment. Meanwhile, a larger and more robust, double-blinded, placebo-controlled phase two trial is under way and a phase three trial is planned to start in the second half of 2024.

The new treatment takes us one step closer to finding an ultimate treatment to normalize hereditary angioedema, which would allow patients to gain control over the disease and regain their lives. On a cautionary note, the researchers pointed out that the therapy affects only the patient and is not passed onto their children, thus leaving children open to the possibility of inheriting the disorder.

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