Potential CRISPR genome editing treatment for transthyretin amyloidosis

The Takeaway: The latest success of a study attempting to knock out the transthyretin (TTR) protein—the gene encoding the symptom-inducing protein related to transthyretin amyloidosis (ATTR)—has many within the genetics field believing we’ve entered a new era of breakthroughs in CRISPR research, one where treatment options for even more challenging genetic diseases might be on the horizon.

What is transthyretin amyloidosis?

Transthyretin amyloidosis (ATTR) is a rare, life-threatening disease impacting about 50,000 people worldwide. While sometimes hereditary, that’s not always the case. In fact, nonhereditary ATTR may be a major contributor to heart failure in people over 50.

ATTR is marked by an accumulation of misfolded TTR protein in tissues, most significantly those found near nerves and the heart. Patients diagnosed with this devastating disease often undergo years of evaluation before landing on the correct disease identification. Given the progressive nature of this disease, early diagnosis is critical. Over the course of a lifetime, the impact on many internal organs—heart, kidneys, liver, spleen, nervous system, and digestive tract—increases and is often extensive.

Mimicking more common diseases, the majority of ATTR patients note a numb-like feeling caused by nerve pain in their extremities. As years pass, this pain often leads to a disability and/or the need for an organ transplant. In the most severe cases, ATTR is fatal.

Currently, there is no cure for ATTR. However, there are numerous treatment options available, including chemotherapy, heart medications, targeted and surgical therapies, and surgical procedures, such as dialysis or transplant to help patients manage and limit the overproduction of amyloid protein. That said, many of these treatments also come with significant risk and side effects, and they do not ultimately cure the disease.

CRISPR in vivo gene editing identified as a possible treatment for ATTR

To understand how CRISPR gene editing may present a new course of treatment options, we’ll need to review the basics of CRISPR.

With a strong foundation established on CRISPR research, a team from the University College London, Royal Free Hospital, led by Dr. Julian Gillmore, hypothesized that CRISPR technology would be beneficial for individuals with ATTR. Their recently published research marks a major milestone in the advancement of CRISPR technology.

The study evaluated the in vivo gene-editing (taking place inside a living organism) therapeutic agent, which researchers have named NTLA-2001, that guides a target sequence into a cell for sequence-specific cleavage of the TTR gene. Once completed, this process would then prevent the accumulation of TTR protein in blood serum over time. The hope is that although the body has already built-up high levels of the TTR protein, removal of the TTR gene using CRISPR technology would dramatically reduce additional accumulation, giving the body an opportunity to clear itself of the excess and return to a closer-to-normal state.

At 28 days post-procedure, blood serum analysis from study participants demonstrated up to 96% reduction in TTR for patients receiving the higher of two doses administered. The repeatable and significant reduction in TTR levels within the outcome data were strong indicators of overall initial success and a groundbreaking advancement in CRISPR technology. The notable achievements from this research were based largely on the CRISPR-Cas9 system, with the addition of a lipid nanoparticle (LNP) that envelopes the Cas9-encoding messenger RNA and the single guide RNA targeting, ultimately knocking out TTR within the cell.

"While these are early data, they show us that we can overcome one of the biggest challenges with applying CRISPR clinically so far, which is being able to deliver it systemically and get it to the right place," said Jennifer Doudna from the University of California, Berkeley and a Nobel Prize winner for her work developing CRISPR, during an interview with NPR.

What other diseases could potentially benefit from CRISPR cures?

Many. The ATTR study serves as a significant proof of concept that CRISPR might be an option for more complicated diseases like heart disease, muscular dystrophy, Alzheimer’s, and even HIV.