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With CRISPR gene editing, unique treatments begin to take off for rare diseases

Researchers and patients are excited about recent advancements, but such experiments have their own sets of risks and challenges

Paddy Doherty receiving his single infusion of CRISPR-based therapy at a London clinic. (Courtesy of Paddy Doherty)

Paddy Doherty remembers his father as a proud, hard-working family man who stayed physically fit for most of his life. A career in construction and various home improvement projects kept him active until his 60s, when Doherty first caught glimpses of a worrying decline in his dad’s health.

“I noticed him getting breathless on walks. He’d stop for a while and maybe make an excuse for stopping, saying, ‘Oh, isn’t that a lovely tree’ or whatever,” said Doherty, who lives in Ireland. Doctors chalked it up to angina, or chest pain caused by reduced blood flow to the heart, symptomatic of an underlying heart problem.

But two years later, when Doherty’s father died of a sudden heart attack, the true cause was discovered: a rare disease called transthyretin (ATTR) amyloidosis, characterized by a misfolded protein that builds up in the heart and interferes with normal function.

“Patients left untreated with this type of amyloidosis develop heart failure, low blood pressure, horrible bowel disturbance, and eventually become incontinent of urine and feces,” said Julian Gillmore, nephrologist and head of the National Amyloidosis Centre at University College London. “It’s a truly awful, gradually progressive disease that is ultimately fatal.”

In February last year, Doherty — now about age 65 — began to experience the same early breathing symptoms his father had had. As an avid hiker who has trekked the Himalayas, he was surprised to find himself getting winded on local hill walks. Testing confirmed that Doherty had a hereditary form of ATTR amyloidosis.

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But there was one bit of good news: If Doherty had been diagnosed even a year earlier, no treatment options would have been available to him — an all-too-common situation for over 30 million U.S. patients with rare diseases. But Gillmore, Doherty’s doctor, offered him the chance to participate in an early stage clinical trial using CRISPR, a groundbreaking genome editing therapy with the potential to cure his ATTR amyloidosis in a single dose.

Groundbreaking therapy

“I had no side effects and left the facility after two days.” Doherty said. “The walk that I felt breathless on, which is a steep kind of mountain walk through a forest, I’m doing that every Sunday now.” CRISPR-Cas9, whose creators were awarded the 2020 Nobel Prize in chemistry a mere eight years after its discovery, allows researchers to alter the DNA of living things at will. It works like genetic scissors that can insert, repair or edit individual genes to rewrite the code of life. The system itself consists of two molecules — a protein known as Cas9 that works like scissors and a guide RNA that takes Cas9 to the right place in the genome — that can be inserted into cells or the bloodstream.

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Now, a growing number of researchers like Gillmore are taking on the challenge to develop CRISPR-based therapies to improve the lives of patients with rare conditions such as cystic fibrosis, Duchenne muscular dystrophy and Huntington’s disease that are caused by mutations in single genes. Almost 1 in 10 people in the United States lives with a rare condition of some kind, most of which have a genetic basis with no treatment approved by the Food and Drug Administration available.

“Broadly, there are more than 7,000 rare diseases impacting over 30 million Americans. Ten or 15 years ago, the technologies to effect change [in terms of treatment] were just not available,” said Rich Horgan, founder and president of Cure Rare Disease, a Boston-based nonprofit group. “But the onset of CRISPR has shown that gene editing has incredible promise, and I think we’re just scratching the surface of what CRISPR will unlock for society.”

In terms of nonhuman applications, CRISPR has already created disease-resistant crops, genetically modified laboratory animals, livestock and new antimicrobials.

Studies to treat a variety of rare conditions in human patients with CRISPR are ongoing, but initial results appear promising.

Promising results

In June, Vertex Pharmaceuticals and CRISPR Therapeutics reported the latest data from small clinical trials testing CRISPR therapy for two rare inherited blood disorders: sickle cell disease and beta-thalassemia. Sickle cell disease, which disproportionately affects Black Americans, is caused by genetic mutations that turn red blood cells from flexible discs into rigid sickles that can block blood flow and cause sudden painful crises. Patients with beta-thalassemia have reduced production of hemoglobin, and patients often require regular blood transfusions.

For both diseases, CTX001 involves removing blood stem cells from patients’ bone marrow, turning on a gene that produces usable hemoglobin and infusing the cells back in. After the therapy, the researchers saw marked improvements in both disease groups for anywhere from three to 26 months of follow-up. All 15 patients with beta-thalassemia, who were previously dependent on blood transfusions, no longer needed them. Similarly, the seven patients with sickle cell disease had no sudden painful crises because of blocked blood flow since the treatment.

“We don’t have the final results of this clinical trial, but so far, it seems to be quite successful,” said Mario Amendola, group leader at Généthon, a French nonprofit research institute dedicated to the development of gene therapy treatments for rare diseases. He was not involved in the study. “The idea is that they use CRISPR-Cas9 not to correct the malfunctioning gene, but to [switch on] a gene that can functionally replace the missing one.”

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In the case of the clinical trial on patients with ATTR amyloidosis Gillmore and his colleagues aimed to not only edit the malfunctioning gene itself but also demonstrate for the first time that direct infusion of CRISPR molecules into the bloodstream is safe and effective.

The hereditary form of ATTR amyloidosis affects roughly 50,000 people worldwide — with a large cluster of patients like Doherty with roots in Donegal County, Ireland. A mutation in the gene that provides instructions for producing the transthyretin protein causes it to misfold and deposit in the body’s tissue and organs, disrupting normal function.

Because circulating transthyretin is made almost entirely in the liver — and everything that enters the bloodstream is carried to the liver to metabolize — the researchers realized they could simply inject patients with the CRISPR-based therapy.

The therapy, called NTLA-2001 and developed by Intellia Therapeutics, appeared to knock out the mutated gene as intended. Only six patients were tested in total, but the three who received the higher of two doses — including Doherty — saw their transthyretin levels drop by an average of 87 percent after 28 days.

The results remain preliminary, and several more patients will need to be tested before the trial is complete.

“It’s important to emphasize that this is very early data, but at the moment, things look incredibly promising,” Gillmore said. “What we will hopefully see over the next five to 10 years is the ability to deliver a therapeutic to not just the liver, but whatever cell you want.”

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Patients with other kinds of rare diseases would need a CRISPR-based drug that distributes itself throughout the entire body.

For example, Horgan founded Cure Rare Disease to develop just this kind of treatment for his younger brother, Terry, who has Duchenne muscular dystrophy, a progressive, muscle-wasting disease. At 26, Terry requires round-the-clock care from his parents to do basic physical tasks such as showering and using the bathroom. His condition stems from a mutation in a gene that provides instructions for making dystrophin, a protein primarily in muscles used for movement and cardiac muscle.

Although FDA-approved therapies exist for some patients with Duchenne muscular dystrophy, Terry’s particular mutation makes him ineligible for those drugs. Few individuals with the disease live past their 30s.

“I wondered if there was anything in clinical development to treat this mutation, and the answer was no, which really scared me,” Horgan said.

Recent research that created a tailor-made drug within less than a year for a 6-year-old girl with a rare, fatal neurodegenerative disorder inspired him to attempt the same feat for Duchenne. He rallied a group of gene therapy scientists to work on a CRISPR-based therapy for Terry’s specific mutation.

The hope is that CRISPR will then boost production of dystrophin in his muscles. “We’ll dose Terry in late winter or early spring,” Horgan said. “We really look forward to that being our first proof-of-concept for subsequent patients that we’ll dose over the coming years.”

Many other strategies for tackling rare diseases with CRISPR are in even earlier stages of research. For instance, Amendola and colleagues are taking somewhat of an opposite approach as Horgan’s team. Instead of creating a drug based on a single patient’s disease, they are developing a modular treatment that could theoretically treat many different conditions.

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7,000 rare diseases

“There are about 7,000 rare diseases, and for each disease, there can be different mutations,” Amendola said. “So if you want to correct every mutation, it will probably take forever. Our idea is to find some kind of strategy which could be adapted — not for all of them, because that’s impossible, and they are too different — but at least for a family of diseases.”

His laboratory is testing a CRISPR-based platform that transforms red blood cells into factories for proteins missing in the blood. Preliminary results in mice appear encouraging for rare conditions like hemophilia B, Hurler syndrome, Fabry disease and Wolman disease.

“We would like to use this as a plug-and-play platform for many different diseases, so that we don’t have to re-optimize the whole system every time,” he said. “We just need to change it a small bit, which hopefully can speed up the drug development process.”

But taking the CRISPR route for rare diseases has its own set of risks and challenges. One possible issue includes minimizing off-target effects that occur when the technology acts on unintended parts of the genome. Also, researchers need to make sure the CRISPR molecules stay in the part of the body that needs treatment. While longer follow-up is still required, subjects in the clinical trials mentioned have not experienced any unexpected harmful side effects so far.

Lastly, the costs of CRISPR-based therapies remain exorbitant at the moment, with price tags exceeding $1 million per treatment.

“For us to be able to continue gene therapy and all that it’s unlocking, it’ll be very important for there to be good conversations around reimbursement of these drugs — not just for customized therapeutics, but for gene therapies as a whole,” Horgan said. “It’s very expensive to make them right now.”

Doherty said he hopes his family members and fellow Donegal residents will be able to benefit from CRISPR as much as he has. Fortunately, testing shows his two daughters did not inherit ATTR amyloidosis. And along with his father, Paddy’s uncle and cousin both died of the disease.

“When the trial is over, I hope that CRISPR is available and affordable for all amyloidosis patients,” Doherty said. “If a pharmaceutical company can mass-produce something like that and sell it at a good price, it would be a godsend.”