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Wednesday, August 10, 2022
Dr. Brown: Valuable lessons learned from treating rare diseases

Sometimes, a rare disease can teach us a lot about treating more common diseases.

Such is the case for a disease called transthyretin amyloidosis, which in its autosomal dominantly transmitted form, is rare – about one case in 100,000.

Chance mutations in the transthyretin gene related to aging and other factors, account for far more common non-genetically transmitted versions of this disease.

Transthyretin is a protein made in the liver whose normal task is thyroxine and vitamin A transport – a prosaic enough job not unlike thousands of other tasks carried out by other proteins in the body whose structures and functions are dictated by their parent genes. So far, so good.

In its normal form, the transthyretin protein is a soluble tetramer made up of four sub-units. However, in its mutant form – a product of mutations in its parent gene – this protein unfortunately breaks up to form fine insoluble amyloid fibrils.

Deposited in peripheral nerves, those fibrils cause loss of sensation, postural drops in blood pressure, incontinence and diarrhea, or deposited in heart muscle, lead to progressive heart failure. And left untreated, the disease is fatal within three to 15 years.

That dismal picture dramatically changed recently because of cumulative and closely related advances in physics, chemistry, molecular biology and genetics, especially in the field of messenger RNA (mRNA) technologies (sound familiar to you what with mRNA vaccines?), and CRISPR-Cas9, a novel gene-editing tool. For the latter, the 2020 Nobel prize in chemistry was awarded to Emmanuelle Charpentier and Jennifer Doudna.

These technologies offer two ways of treating both the genetically transmitted and naturally occurring (wild) mutant forms of this disease. The first approach involves mRNA.

Normally, genes that code for specific proteins are transcribed into a single strand of mRNA in the nucleus, the code of which mRNA, is read (translated) by ribosomes in the cytoplasm to create gene-specific proteins. That train of events from gene to protein offers a way to treat diseases like transthyretin amyloidosis by blocking the go-between mRNA molecule and thereby stopping the production of the mutant protein responsible for the disease. Nifty.

That’s what was achieved with two new drugs, Inotersen and Patisiran in 2018. Repeated injections with Inotersen or intravenous infusions in the case of Patisiran over the course of a year and a half dramatically reduced the blood levels of the mutant protein.

More importantly, progression of the disease was halted and even reversed. That’s the good news. The not-so-good news would be the high cost and inconvenience of repeated treatments and, more importantly, occasional severe adverse side effects.

The triumph in the treatment of transthyretin amyloidosis was the recent evidence that CRISPR-Cas9 was found to be equally, if not more, effective in lowering the blood levels of the mutant transthyretin protein compared to the mRNA treatments. But unlike the latter, it was associated with only minor side effects and required but one treatment.

The CRISPR part of the CRISPR-Cas9 was a short strand of RNA tailored to target the mutant transthyretin gene, while avoiding any off-target misses of functional significance. The CRISPR guide was coupled to an enzyme (Cas9) to cut the gene at both ends of the target site. That effectively knocked out the mutant gene.

It worked in part because CRISPR-Cas9 was packaged in a nanoparticle-sized lipid shell engineered to evade the immune system in much the same way Pfizer and Modern protected the RNA in their COVID vaccines. In the case of treating transthyretin amyloidosis, the CRISPR-Cas9 package was also designed to target the liver.

Follow-up, of course, is needed but the triumph is impressive for the high level of collaboration shown by so many disciplines in universities and high-tech companies. That’s often what it takes these days.

This review spotlights one of a growing number of single mutant gene-related diseases that were hitherto untreatable by employing novel technologies to edit the mutant gene responsible for the disease directly using the gene-editing tool CRISPR-Cas9 or, alternatively, to block the effects of the mutant gene on protein production by interfering with the mutant mRNA.

Gene therapy is a rapidly growing game-changing tool for treating cancer, common inherited blood disorders such as sickle-cell disease and thalassemia, some eye diseases, inherited genetic diseases of the brain such as progressive muscular atrophy in infancy, and several muscle diseases.

For all those and other reasons, gene therapy is the subject of the opening program in the InfoHealth series on Sept. 13 at 11 a.m. in the Niagara-on-the-Lake library. In-person attendance is limited to 20 people.

Remember, too, the Nobel series returns on Monday, Nov. 8 at 11 a.m.

Dr. William Brown is a professor of neurology at McMaster University and co-founder of the InfoHealth series at the Niagara-on-the-Lake Public Library.