Amyloid is an abnormal protein that infiltrates the heart, kidney, liver and nervous system.
When deposited in the heart it causes right heart failure, heart block, and ventricular tachycardia.
Cardiac amyloidosis is a fatal disease that substantially shortens one's life span to 2 to 6 years.
Cardiac amyloidosis, however, is not a rare disease.
15% of “low flow low gradient aortic stenosis “patients have cardiac amyloidosis.
15% to 30% of patients with diastolic heart failure have cardiac amyloidosis
Cardiac amyloidosis is diagnosed by ECG showing small QRS complexes, by 2D echo showing thickened ventricular walls, thick interatrial septum, and thickened valves. There is also evidence of reduced ventricular filling.
Cardiac MRI shows patchy late gadolinium enhancement.
There are 2 kinds of amyloidosis, one caused by light chain immunoglobulins, and the other is TTR or transthyretin amyloidosis. TTR amyloidosis can be either acquired or inherited.
Inherited TTR amyloidosis is due to more than 100 mutations in a TTR gene in the liver.
Drug therapy for TTR amyloid has not been too successful.
The NEJM last week published a pilot study in 6 patients with inherited TTR amyloidosis. This is a landmark trial because this is the first time the CRISPR-Cas9 system has been used in patients with inherited TTR amyloidosis
An IV injection with a CRISPR- Cas 9 gene editing system was given. This is a complex of a guide RNA and Cas 9 enzyme in a nanoparticle. The guide RNA carries the gene-editing enzyme Cas9 to the gene in the liver, where it cuts the TTR gene. The cut gene can no longer produce TTR protein.
In 28 days there was an 87% reduction in TTR levels, one patient had a decline of 96%.
Adverse effects were mild, few, and brief. Only a single shot is required.
It is imperative of course that more trials. are done to confirm the safety and efficacy of this pilot study using the CRISPR-Cas 9 system, which was discovered in a bacterial immune system.
The Nobel Prize in Chemistry (2020) was awarded to two women scientists who transformed a bacterial immune mechanism, commonly called CRISPR, into editing the genomes of everything from wheat to mosquitoes to humans.
The award went jointly to Emmanuelle Charpentier of the Max Planck Unit for the Science of Pathogens and Jennifer Doudna of the University of California, Berkeley, “for the development of a method for genome editing.”
CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis
https://www.nejm.org/doi/10.1056/NEJMoa2107454
