Is Sangamo’s gene-editing approach a failure?


Therapeutic Sangamo(NASDAQ: SGMO) The zinc finger nuclease approach to gene editing has been touted as a potential solution for millions of people with genetic disorders; but the company still hasn’t produced any commercial-stage therapy, even after more than 20 years of research. Unfortunately, the company’s track record became more disappointing on Thursday when management announced poor results from a preliminary trial evaluating SB-318 gene editing therapy in people with type I mucopolysaccharidosis (MPS I).

A significant unmet need

People with MPS I, or Hurler’s syndrome, face a poor prognosis. Lysosomal overload disorder, caused by genetic mutations that interfere with the production of the enzyme alpha-L-iduronidase (IDUA), occurs in 1 in 115,000 births.


IDUA is essential for breaking down the glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate. Because people with MPS I cannot metabolize these complex carbohydrates normally, they experience life-shortening organ damage as the substances build up.

People with the severe form of the disease usually die in childhood, and people with the mild form usually do not live long beyond their 30s. BioMarin‘s (NASDAQ: BMRN) Enzyme Replacement Therapy (ERT) Aldurazyme is the only treatment currently available, but life expectancy remains short despite the existence of therapy.

How Zinc Finger Nuclease Works

Zinc finger nuclease (ZFN) is a unique approach that attempts to functionally cure a genetic disease by altering genes to restore normal activity.

The approach uses zinc finger DNA binding proteins to guide Fok1, a cutting enzyme, to a specific target in a person’s DNA. To make a modification, two ZFNs are constructed, each containing half of the cutting enzyme Fok1. The ZFN pair binds to either side of the targeted DNA, and when the two halves of Fok1 combine, a cut is made, allowing the new code to be inserted.

In the case of MPS I, Sangamo’s SB-318 inserts a functional copy of the IDUA-producing gene into the liver so that the individual can produce IDUA in their body, thus eliminating the need for ERT infusions, essentially curing the patient.

There is little to like in the data

The idea that the SB-318 could restore IDUA production may be off target given data released by Sangamo this week. In those receiving the treatment, there was no evidence of a sufficiently significant increase in IDUA activity to suggest that this is an effective treatment.

Sangamo Therapeutics will analyze liver biopsy tissue to see if there is evidence of successful genetic modification, and it plans to continue evaluating patients, including removing them from ERT treatment, to further assess effectiveness. .

Sangamo’s latest trial update is not encouraging, especially as the company reported data last year showing little benefit from SB-913 in MPS II, or Hunter syndrome. . People with MPS II cannot make the enzyme iduronate-2-sulfatase necessary for the breakdown of GAGs. Similar to study SB-318, SB-913 attempts to insert a functional gene into the liver to restore enzyme production.

Check out the latest transcript of Sangamo’s earnings call.

What to watch next

Sangamo Therapeutics’ Zinc Finger Nuclease Approach is hard to come by. The company’s trash can is littered with test failures over the past two decades; it does little to inspire investor confidence. There is still a chance that this company could prove that its gene editing approach works, but if that doesn’t happen soon, it could lose its lead in gene editing in favor of other approaches, including CRISPR / Cas9. Ultimately, there are over 6,000 genetic disorders and many have no treatment options; I hope that will change. Whether Sangamo’s approach is the solution, however, remains unclear.

This article represents the opinion of the author, who may disagree with the “official” recommendation position of a premium Motley Fool consulting service. We are heterogeneous! Challenging an investment thesis – even one of our own – helps us all to think critically about investing and make decisions that help us become smarter, happier, and richer.

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