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Genetic Linkage

Second Gene Therapy Nears Approval in Europe: Lessons for CRISPR?

CRISPR-Cas9 gene editing has been around not even 4 years, and people are avidly discussing its promises and perils. That’s great. But consider the historical backdrop.

April 1, the European Medicine Agency’s (EMA) Committee for Medicinal Products recommended for marketing approval a second gene therapy. “Strimvelis” treats adenosine deaminase severe combined immunodeficiency syndrome (ADA-SCID) and was developed at the San Raffaele Telethon Institute for Gene Therapy in Milan and GlaxoSmithKline. Regulatory approval is expected within a few months.

I wonder how many people realize, especially those fearful of how gene editing might be misused, that the gene therapy that is nearing approval actually entered clinical trials 26 years ago?

Yes, it took more than two decades to approve the first gene therapy. It was Glybera, approved in Europe in late 2012 to treat lipoprotein lipase deficiency. Clinical trials to test any drug are extremely difficult to design, implement, and sometimes interpret, and this is especially true for a gene therapy, technically termed “gene transfer” until efficacy is clear. The first gene therapy approval in the US may happen this year, but probably next.

ADA-SCID is NOT Bubble Boy Disease

The media, in reporting the April 1 EMA recommendation, widely dubbed ADA-SCID “bubble boy disease,” from the Wall Street Journal to Fortune and even to Medscape. IT’S NOT.

The real bubble boy, played by John Travolta in a TV film and ridiculed by Jerry Seinfeld in the 47th episode of his eponymous TV show, had a name. David Vetter had SCID-X1, which results from a mutation in the interleukin 2 receptor subunit gamma (IL2RG). ADA-SCID is an enzyme deficiency and a more systemic illness.

Both ADA-SCID and SCID-X1 cripple T cells and therefore also B cells -- that’s what the “combined” in the name means -- but by entirely different mechanisms. ADA-SCID is autosomal recessive, SCID-X1 X-linked. The true bubble boy disease is the one that ran into trouble when a gene therapy vector pierced an oncogene, causing leukemia in some of the young boys in a clinical trial – a problem addressed by retooling vectors.

The true hero of the ADA-SCID story is actually a heroine, Ashanthi (“Ashi”) DeSilva. She was 4 when she received the very first gene therapy of any kind – at the NIH in Bethesda, in 1990. I tell Ashi’s story in my book about gene therapy, and excerpt it for Rare Disease Reports.

Notes From a Gene and Cell Therapy Meeting

Several research groups have been working on a combination stem cell and gene therapy for ADA-SCID for many years. The approach is ex vivo (cells doctored outside the body) and autologous (patient receives her own cells).

Several investigators very graciously presented combined data at a press conference at the American Society of Gene & Cell Therapy annual meeting two years ago. At that time, 42 children had been treated, 18 from Milan, 8 from London, and 10 from Children’s Hospital Los Angeles/UCLA. The protocols used gamma retroviruses as the vector, with 100% survival and 73.8% disease-free survival.

Adrian Thrasher, PhD, from the University College London Institute of Child Health Great Ormond Street Hospital for Children, justified the new treatment for a disease so rare that it affects only 15 children in Europe a year. “Doing the math for ADA deficiency is easy. It costs $500,000/year for the enzyme replacement therapy, PEG-ADA. Autologous delivery is just the cost of a short hospital stay.” The children in the trials did not have matched bone marrow or umbilical cord stem cell donors. Many received PEG-ADA until the gene therapy took hold, as did Ashi in the initial trial, for safety.

Other speakers described a patient who contracted a cytomegalovirus infection after the gene therapy and fought it off so well that he didn’t even need acyclovir, and another whose liver enzymes and ADA levels were better than those of the researchers. And none of the kids showed a predominance of one white blood cell subtype that would indicate the feared leukemia.

At the news conference I asked about Ashi, because in researching my book I knew that some researchers questioned whether her gene therapy had really worked, since she was also receiving the enzyme. Other glitches, seen in retrospect, were that the gene transfer works better on babies, and that stem or progenitor cells are better targets than were Ashi’s mature T cells. “The study used the best tools they had at the time. It was not enough to provide a clinical benefit, but there’s no question that by using the new methods, patients definitely have a clinical benefit. No one uses the word “cure,” but great clinical benefit,“ said Harry Malech, MD, Chief of the Genetic Immunotherapy Section at the National Institute of Allergy and Infectious Disease, who led the session.

History in a Citation List

So what is the new method for effectively delivering healing genes? A look at the citations from Don Kohn, MD, who leads the UCLA group, traces the evolution of ADA-SCID gene therapy, while also illustrating the incremental nature of science in general and the hurdles to get gene therapy up and running in particular.

1986 Retroviruses deliver working ADA genes to human T cells in culture

1989 T cell lines are established from an ADA deficient patient

1995 Functional ADA genes are introduced via CD34+ cord blood stem cells to three newborns, one of whom graces the cover of Time magazine, with sustained gene expression.

1998 The three little boys are now three years old, and 1 to 10% of their T cells bear the correction.

2003 The boys still have corrected T cells, but not the explosive leukemia from SCID-X1 gene therapy that appeared in 2002. Just to be safe, further children with ADA-SCID treated in 2005 and later had genes delivered in retooled retroviruses, and also received a drug that makes more room in the bone marrow.

2006 Lentivirus delivers human ADA gene into knockout mice. Lentivirus (disabled HIV) is replacing gamma retroviruses in some gene therapy experiments.

2014 The lentivirus mouse model corrects the enzyme deficiency.

2016 “New approaches to gene therapy for ADA-deficient SCID, including the use of lentiviral and foamy viral vectors for ex vivo gene transfer to hematopoietic stem cells, direct in vivo ADA gene delivery and ADA gene correction using site-specific endonucleases to augment homologous recombination,” according to Dr. Kohn’s website.

Déjà vu All Over Again

Descriptions of the early ADA-SCID gene therapy experiments eerily parallel today’s concerns about CRISPR-Cas9. Consider "Human Gene Therapy", a 1992 paper in Science by William French Anderson, MD, who treated Ashi. He wrote, "It’s important to distinguish between gene therapy, which adds a gene but does not remove the mutant one, and gene/genome editing, which swaps in a gene or genes. Done on somatic cells the technologies would provide treatments; done on fertilized ova, the germline, they’d alter individuals."

In 1992 Dr. Anderson discussed human germline manipulation, but then ironically pointed out that an intervention that uses the general gene swapping phenomenon called homologous recombination would actually be safer because it is much more precise. CRISPR-Cas9 does that. He wrote, “Until the time comes that it is possible to correct the defective gene itself by homologous recombination (rather than just inserting a normal copy of the gene elsewhere in the genome), the danger exists of producing a germline mutagenic event when the ‘normal’ gene is inserted. Therefore, considerable experience with germline manipulation in animals, as well as with somatic cell gene therapy in humans, should be obtained before considering human germline therapy.”

If that wasn’t prescient enough, Dr. Anderson then brought up:
• An infant’s right to an unmanipulated genome
• The impossibility of a fertilized ovum providing informed consent
• Playing God
• Genetic enhancement

Dr. Anderson can’t directly share his joy at the EMA announcement because he has been in prison since 2007. I’ve told some of his story here, and a more recent account is here. He told me that he is “delighted that the approval in Europe is going forward.”

Genetic Illiteracy
Given the time it’s taken to get the first gene therapies into the clinic, I don’t think CRISPR-Cas9 DIY DTC kits will festoon the shelves at Walgreens anytime soon. But due to the relative ease of gene editing compared to gene therapy, it shouldn’t take two decades.

In the meantime, I hope that the media and public opinion polls make the effort to distinguish the two biotechnologies.








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