Inishowen man takes part in world first clinical trial seeking Amyloidosis cure

Last year, James Green from Burt, was told he carried the rogue gene that could lead to hereditary Amyloidosis, which had already claimed the lives of some of his family.

ATTR amyloidosis is a progressive and fatal disease that usually requires chronic, lifelong treatment.

Amyloid deposits accumulate in multiple tissues, including the heart, nerves, and GI tract leading to complications such as polyneuropathy (ATTRv-PN) and cardiomyopathy.

In recent weeks, Intellia Therapeutics, Inc. and Regeneron Pharmaceuticals, Inc. announced the results of a Phase 1 trial which indicate that a long-awaited cure could be found.

The companies announced how there has been ‘positive interim data’ from their clinical study of their lead ‘in vivo genome editing candidate, ‘NTLA-2001, which is being developed as a single-dose treatment for ATTR amyloidosis.

It is the only one-time treatment in development for the disease.

James and fellow Donegal man Patrick Doherty, from Gaoth Dobhair were two Donegal men who took part in the first phase of the trial, which was led by the UCL Amyloidosis Centre in the Royal Free Hospital in London. Amyloidosis is so prevalent in the county, it is known as ‘Donegal Amy’.

In James’ case, his results show that the protein that can cause the disease has more than halved since he received the drug infusion.

In a press release, the companies outlined how NTLA-2001 ‘is the first CRISPR/Cas9-based therapy candidate to be administered systemically, via intravenous infusion, for precision editing of a gene in a target tissue in humans.’

Patients in the trial received a one-off infusion of the CRISPR/Cas-9 molecule, which allows scientists to make precise changes in DNA.

NTLA-2001 is designed to inactivate the TTR gene in liver cells to prevent the production of the misfolded transthyretin (TTR) protein. It is this misfolded protein that accumulates in tissues throughout the body and causes the debilitating and often fatal complications of ATTR amyloidosis.

NTLA-2001 shows strong potential in stopping the production and accumulation of this TTR protein by inactivating the TTR gene, which is at the very root of the disease.

Results of the first phase show that levels of the misfolded protein had been reduced by up to 96% in one patient, with very positive findings. There were also no serious side effects reported.

James told the ‘Journal’ how his results so far and the reduction of the protein he already received, should be enough to keep his Amyloidosis stable.

He outlined how he learned he carried the ‘rogue gene’ that could lead to the condition.

“Last summer, I decided the time was right to have a genetic test to see if I carried a rogue gene that could cause me a life threatening condition, hereditary Amyloidosis. I arranged though my GP for a blood sample to be sent to the Royal Free Hospital in London and after about six weeks my positive carrier status was confirmed. I knew the gene was in the family as it had already devastatingly taken the lives of an aunt, uncle and cousin.”

James told how early diagnosis through genetic testing ‘is key to survival as often patients are diagnosed only when large scale disease has set in.’

“ A DPD scan at the Mater in Dublin confirmed that trouble was coming at me, and this led to a referral to Professor Julian Gillmore at the Centre of Excellence for Amyloidosis patients at the Royal Free in London. I had heard of an upcoming Crispr clinical trial and when it launched late last year I didn’t hesitate to enrol in phase 1 of the trial.

“Thankfully, following an intensive two week screening process at the Royal Free and Richmond Pharmacy, London, I received my Crispr drug infusion on January 22 this year. The Crispr trial is the ‘first in human gene editing drug’ to be administered by infusion directly in to the body. Since January my TTR level, the protein which can miss fold and cause the disease, has more than halved. The drug works as a mini pair of scissors, it searches out the defective DNA in the liver cells that produce TTR, cuts it out, halting the production of TTR and hopefully the progression of any disease.”

James is hoping to receive a ‘top up’ of the drug once the details of phase two have been confirmed.

“I’m fortunate that Intellia are committed to giving me a full dose of the Crispr drug once the optimum therapeutic dose for phase 2 has been determined. I’m hopeful that will be later this year. The top up aims to achieve an even greater reduction in my TTR, close to a complete knock down to under 5%. The reduction already achieved should be enough to keep my amyloid stable, meanwhile.”

The results of Phase 1 are ‘groundbreaking,’ said James.

“The publication of the Crispr report in the New England Medical Journal on the efficacy and safety of the trial was a ground breaking in the field of medicine. I’m very thankful to Professor Gillmore, Intellia, and the team at Richmond Pharmacology for the opportunity to take part in the trial. It’s exciting to see a cure for hereditary Amyloidosis on the horizon, however the trial will move ahead with caution. If all continues to go well it will be some years distant before CRISPR is generally available.”

Meanwhile, patients in the South of Ireland do not have access to gene-silencing treatments such as Patisiran and Inotersen, which, are available throughout the UK and Europe, and many countries worldwide.

James said: “We need that to change without delay.”

Intellia Therapeutics is a gene-editing company co-founded by Nobel laureate, Jennifer Doudna.

The encouraging results were presented at the 2021 Peripheral Nerve Society (PNS) Annual Meeting and simultaneously published in The New England Journal of Medicine.

“These are the first-ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of CRISPR. The interim results support our belief that NTLA-2001 has the potential to halt and reverse the devastating complications of ATTR amyloidosis with a single dose,” said John Leonard, President and CEO of Intellia.

“Solving the challenge of targeted delivery of CRISPR/Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline. With these data, we believe we are truly opening a new era of medicine.”

This is exciting early data both for people living with this devastating disease and for the entire scientific community working to maximize the potential of genetics-based medicines through cutting-edge research and technologies,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron.

“Thanks to large-scale human genetics research, there have been many new genetic targets identified and confirmed to have an impact on human health. Combining this knowledge with the precision and enhanced convenience of a single CRISPR infusion unlocks new possibilities in treating – and potentially even curing – life-threatening and historically difficult-to-address diseases.”

“These interim Phase 1 data support NTLA-2001 as the only one-time treatment either on the market or in development,” said Julian Gillmore, M.D., Ph.D., Professor of Medicine, National Amyloidosis Centre, UCL Division of Medicine, Royal Free Hospital.

“As the first-ever systemically administered CRISPR therapy candidate, NTLA-2001 shows strong potential to stop the production and accumulation of the misfolded TTR protein by inactivating the TTR gene at the root of the disease. This approach could deliver life-changing, lifelong benefits to patients with all forms of ATTR amyloidosis, who continue to experience debilitating symptoms and complications of disease while on the standard of care. While further investigation is needed, these results are highly encouraging.”