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Treating Genetic Diseases in Utero Could Change the CRISPR Space

CRISPR stocks have been plagued with clinical holds by the FDA. But what if the treatments these speculative companies are working on can be applied in utero? New research shows they can

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Matt Winkler
Oct 14, 2018
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Genetic disorders are quite a daunting disease group to treat, but there is one major overlooked advantage in developing treatments for this disease group over others. Genetic diseases can be screened for in utero. So what? Thanks to new research published in the journal Nature Medicine, we know that they can be treated in utero as well.

This could have profound implications for the CRISPR gene-editing investment space, because it could change the regulatory landscape for the whole CRISPR approach to treatment. For better or for worse, fetuses do not have the same rights as those already born, and therefore the regulations guiding fetal treatments are different.

As to the latest research, in the most recent issue of Nature Medicine, two animal studies were published, one featuring the CRISPR-Cas9 gene editing system for treating phenylketonuria , and the second featuring a system called base editor 3 to treat the liver disease tyrosinemia type 1, or HT1. Both systems were applied in an attempt to edit and fix the faulty genomes causing the conditions. Both preclinical studies saw surprising success.

The first study was performed in Zurich, Switzerland, featuring a CRISPR-Cas9-based treatment for phenylketonuria (PKU), a disease where a patient’s genes do not code for the enzyme required to break down the amino acid phenylalanine. There is only one treatment for PKU on the market, BioMarin’s (BMRN) Palynziq, but it costs about $200,000 a year and it comes with a black box warning because 9% of patients in a phase III trial suffered anaphylaxis from it. The only other way to manage the disease is to stay away from foods containing phenylalanine. (The next time you pick up a Diet Coke for example, notice the warning label for phenylketonurics.)

How does the treatment work? An enzyme called cytidine deaminase is attached to the CRISPR-Cas9 system delivered by an adenovirus vector. Adenovirus infects liver cells, which are the ones malfunctioning in phenylketonuria. The virus injects the CRISPR-Cas9 with the enzyme attached to it. The enzyme binds to the specific base pair where the genetic error causing PKU occurs, the CRISPR-Cas9 system breaks the DNA at that point, swapping a cytosine-guanine pair with a thymine-adenine, which corrects the error. The researchers found that 60% of all liver cells were corrected in this way in mice, allowing them to digest phenylalanine, showing no signs of the disease.

The second experiment, was out of the University of Pennsylvania . Here, fetal mice with the liver disease hereditary tyrosinemia type 1, were treated with a slightly different form of CRISPR. Tyrosinemia is basically the same thing as PKU but for the amino acid tyrosine instead of phenylalanine. There is a treatment for the disease, a drug called Orfadin (nitisnone) which breaks down tyrosine, but it’s over $300 a pill and must be taken for life. Fix the cells, though, and fix the problem.

This treatment also used an adenovirus vector to shuttle in a type of CRISPR system called base editor 3, which doesn’t completely sever the DNA at the editing point, but leaves one bond intact on the DNA strand after a single-strand break. This way the DNA can be repaired without it being glued back together incorrectly, which could cause worse problems.

Researchers found that fetal mice treated in this way retained their edited liver cells and were healthier than mice with the same disease treated with nitisinone.

Right now, the three CRISPR pure-plays, Editas (

EDIT, Financial), CRISPR Therapeutics (CRSP, Financial) and Intellia (NTLA, Financial) have nothing in the pipeline targeting fetal treatment. That could soon change, changing the whole space. CRISPR Therapeutics, for example, has been plagued with clinical holds of its trials recently, hurting the stock and slowing the company’s progress. For fetal treatments, these clinical holds would be much less likely.

All three stocks are down significantly from highs, and all three are speculative and volatile. Investors interested in following them though should keep an eye out regarding any of them moving to the fetal arena.

Disclosure: No positions.

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