Background
The emergence of gene editing technologies is enabling new therapeutic approaches for complex genetic diseases. New Zealand Clinical Research (NZCR) has played an integral role in this field. New Zealand has become a go-to destination for gene modification studies. Over the last decade, NZCR has been at the forefront of innovation, contributing to a steady stream of breakthroughs—from CRISPR/Cas9 and base editing, to gene silencing, RNA modification, and epigenetic modulation. These advances are part of a commitment to helping deliver tailored medicines in areas of great medical need.
In 2020, during the COVID-19 pandemic, Professor Edward Gane and the team at NZCR played a pivotal role in the world’s first in vivo gene-editing study. This research involved the direct administration of a CRISPR/Cas9 gene-editing system into the bloodstream of patients with Familial Amyloid Polyneuropathy (FAP).
What is Familial Amyloid Polyneuropathy (FAP)?
Familial Amyloid Polyneuropathy (FAP) is a genetic disorder. It is caused by a mutation in the TTR gene, which can be inherited from either parent. This gene provides instructions for making the transthyretin protein. Normally, transthyretin is produced in the liver and circulates in the blood to transport vitamin A and thyroid hormone. In FAP, the mutation in the gene leads to an abnormal transthyretin protein that misfolds and accumulates as amyloid deposits. These deposits can damage nerves and other organ systems, eventually leading to liver failure.
What is CRISPR/Cas9?
CRISPR/Cas9 is a gene-editing tool that has revolutionised genetic research. It functions like a precise pair of molecular scissors, allowing for the addition, removal, or modification of specific DNA sequences. The system uses a guide RNA to lead the Cas9 enzyme directly to the target DNA. At the designated site, Cas9 makes a precise cut, initiating the editing process. In this specific study, the gene-editing technology was delivered to the liver via lipid nanoparticles to inactivate the TTR gene.
The Challenge
“Gene editing brings huge opportunities for medicine, but also big challenges, both morally and ethically.”
— Professor Edward Gane, Hepatologist, NZCR
Gene editing was a new frontier for New Zealand, and the NZCR team worked diligently to ensure all appropriate ethical and regulatory processes were in place.
The regulatory framework, along with the established Gene Technology Advisory Committee (GTAC), enabled a fast and streamlined review. This led to approval from both the Health and Disability Ethics Committee (HDEC) and GTAC in just 8 weeks, a timeframe crucial for a timely study setup.
The Approach
With the regulatory challenges overcome, NZCR’s approach focused on the logistical and safety complexities of being an integral part of the world’s first in vivo gene-editing study. The protocol required a minimum 14-day dosing interval between patients, an important safety measure for this first-in-human study. The team at NZCR carefully coordinated patient dosing with other international sites, a key step in successfully dosing the world’s second patient in the trial.
Outcome
On January 11, 2021, NZCR successfully dosed the world’s second patient—the first in the Southern Hemisphere. In total, 36 patients were enrolled and dosed in this study, with 13 from NZCR. These patients will eventually enter the study’s long-term extension phase, where their safety will be monitored for a further 15 years in accordance with FDA requirements.
Following this success, NZCR has become a prominent location for other gene-editing studies. It has since conducted two other gene-editing studies in patients with Hereditary Angioedema (HAE) and Heterozygous Familial Hypercholesterolemia (HeFH), with more studies currently at the regulatory stage. These efforts have positioned NZCR among the leading gene-editing centres globally.
Why New Zealand?
Sponsors choose New Zealand for gene editing and gene modification research because of several unique advantages.
- Supportive environment: Strong political and societal support for gene technology, including the establishment of the Gene Technology Advisory Committee (GTAC) specifically to review these studies. This supportive environment contributes to competitive regulatory approval timelines.
- Experienced investigators: Principal Investigators with significant expertise across liver disease, cardiology, immunology, endocrinology, and haematology. Professor Edward Gane’s internationally recognised liver expertise is particularly important given the liver’s central role in many gene modification technologies to date.
- Proven track record: More than 30 studies successfully delivered over the past 15 years, beginning with gene silencing approaches.
- Specialised expertise: Extensive experience in managing the toxicities associated with advanced gene technologies, including lipid nanoparticle-related effects such as transaminase elevations and infusion-related reactions.
Key Achievements
- Pioneering Role: NZCR played a pivotal role in the world’s first in vivo gene-editing study, dosing the world’s second patient and the first in the Southern Hemisphere.
- Unique Advantage: The combination of NZCR’s expertise and New Zealand’s supportive regulatory framework enabled rapid approval in just 8 weeks.
- Global Leadership: This success has positioned NZCR as a leading global centre for gene-editing research, offering outstanding speed, quality, and results.