Science & Medicine

Gene edited SCT is already here

Gene editing for blood disease? 
No problem — it’s already happening!

When gene editing comes to MPN therapy, it will not be its first clinical application. And CRISPR/Cas9 won’t be the first editing tool.  Clinical trials for gene-edited therapies for blood disorders are already wrapping up. And more are in the works.

Today,  people are walking around clear or awful diseaes like HIV because of successful insertions or deletions into DNA.  In fact, the history of gene editing pre-dates the discovery of CRISPR/Cas9.  Because of the intense need for treatment of diseases like HIV, hemophilia, and sickle cell anemia — and because blood is such a readily available tissue —  gene editing of human hematopoietic stem cells has advanced earlier and further than other human in vivo application.

At the Cold Spring Harbor Laboratory’s genome engineering meeting, Dr. Fyodor Urnov, of Sangamo Biosciences, reported on the disruption of HIV infection through editing of the CCR5 gene.

Fyodor Urnov (L.) in discussion at CHSL

Fyodor Urnov (L.) in discussion at CHSL (photo courtesy of Cold Spring Harbor Laboratories)

CCR5 is a chemokine receptor on the surface of white blood cells. While its function as part of the immune system is to attract T cells to cellular targets, its function as a gatekeeper makes it an easy entry point for the HIV, AIDS-causing virus.

HIV and leukemia?  Call me lucky.

One patient,Timothy Brown, had been on anti-retroviral drugs to treat his HIV for 10 years before he was diagnosied with Acute Myeloid Leukemia.  In his ensuing bone marrow transplant he was treated with stem cells that contained the CCR5 mutation on both strands of DNA.  At the end, he left the hospital cured of both diseases…and remains clear of HIV six years later. This experience spurred research to knock out the CCR5 gene.

Discovery that some populations, due to mutation in CCR5, were naturally immune to HIV, led a number of drug companies to field CCR5-inhibitors with little or no success. It took the scissors of gene editing in the form of zinc finger nucleases to mutate the gene.   Ex vivo, these mutated cells were expanded before reintroduction into a patient following full ablation.

Working with the NIH and the California Institute for Regenerative Medicine (CIRM), California’s stem cell agency, Sangamo Biosciences has applied gene editing to other blood disorders like hemophilia and beta-thelassemia , some of which are in or pending clinical trial.

The HIV work, extending back to the first FDA approved IND in 2009,  (  NCT00979238) introduced interruption of the CCR5-inhibition via zinc finger nuclease edited HSCs. Since that time over 70 patients have been successfully treated.

“We have subjects, “said Urnov, “who have stopped taking their antiretroviral drug and are controlling their viral load without any medication.  The longest a subject on the trial has gone without having to take retroviral drugs is 71 weeks. Think about it. This person was 24 years  old and either faced the prospect of taking expensive and side effect-laden drugs the rest of his life or simply experience this clinical benefit.”

Hemophilia B

Sangamo’s work in Hemophilia B is “an alternative to the $500,000 annual cost of protein replacement delivery,” currently the alternative.  The villain: Loss of factor IX (FIX) synthesis.  In 2011, publication of a study in Nature, In vivo  established proof of concept. Next step was to obtain NIH approval for human trial aimed at restoring FIX synthesis through genome editing.

The Clinical trial Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B (NCT00979238) description lays out the case for gene editing.  Hemophilia B is caused by an absence or abnormality in the gene that produces the factor IX protein.City of HOPe slide URno Affected individuals cannot make a blood clot effectively and suffer from severe bleeding episodes. Repeated bleeding episodes, specifically into joints, can cause chronic joint disease and lead to disability.

According to the Phase I protocol, “This research study will test the safety of giving an affected individual a normal factor IX gene which can produce factor IX protein in his body. We will give the normal gene for factor IX by using an inactivated (not able to function) virus called “the vector.” The vector used in this study was developed from an adeno-associated virus that has been changed so that it is unable to cause a viral infection in humans. This inactivated virus was further altered to carry the factor IX gene and to locate within liver cells where factor IX protein is normally made.”

Gene editing in myeloproliferative neoplasms– The CREATE Seminar

CRISPR-Cas9 could not have been used to edit the CCR5 in these  gene editing efforts.  The Sangamo program started nine years ago and CRISPR/Cas9 for all its widespread use is only three years old!

Today, work across multiple blood genetic diseases is being done by several well funded corporations like Editas, CRISPR Therapeutics, Intellia and giant Johnson and Johnson’s Transposagen. When this Sangamo work began, Zinc Finger nucleases were the scissors of choice. Today increasingly accurate and powerful CRISPR enzymes are available to follow the same path:  Apheresis of hematopoietic stem cells, correction of mutation through ex vivo gene editing and reintroduction into the patient in an autologous trnasplant procedure.

The CREATE seminar — sponsored by the MPN Research Foundation and MPN Genetics Network — will be held two months from now in association with this year’s ASH meeting. The seminar brings together MPN and transplantation specialists with synthetic biologists and genetic engineers to explore  steps necessary to get MPN gene editing into clinical trial.

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