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Today’s gene therapy and its cost can only be understood in the context of its tangled history. Starting with promise in the 1980s, gene therapy got over-hyped in the 1990s until 1999 when two unanticipated tragedies in quick succession caused researcher and funding flight, and research stagnation during the 2000s. The first death attributed to gene therapy, Jesse Gelsinger, and the first cancers directly attributed to gene therapy, when French SCID (Severe Combined Immunodeficiency Disorder) children treated with gene therapy developed leukemia, these two events increased regulatory burden, reduced the players in the field, investors fled, and timelines and costs increased. Resurgence began with modest successes in 2008, accelerating with the 1st EU gene therapy approval in 2012.

I. Jesse Gelsinger: Insufficiently road-tested gene therapy could cause death
Jesse Gelsinger was diagnosed with a rare genetic disorder called ornithine transcarbamylase deficiency (OTC). ~ 1 in 40000 babies are born with OTC (1), which prevents breakdown of ammonia, a normal metabolic byproduct. Untreated ammonia build up can eventually damage the brain, leading to coma and death. Jesse’s OTC was milder, controllable by strict diet and medication.

Having been rejected when he’d tried to sign up a year earlier, as soon as Jesse turned 18, he signed up for a UPenn (University of Pennsylvania) gene therapy Phase I clinical trial, conducted by its General Clinical Research Center, with PI (Principal Investigator) Dr. Mark L. Batshaw, co-investigators Drs. James M. Wilson and Steven Raper.

On September 13, 1999, Jesse was injected with 3.8 trillion adenovirus particles (2), considered the highest adenovirus dose ever given. Adeno, then a common gene therapy vector (carrier), is typically associated with the common cold and conjunctivitis. In Jesse’s case the vector was a partially inactivated adenovirus in which the OTC gene had been inserted. It was directly injected into his hepatic artery to ensure direct delivery into the liver, liver cells being the target for OTC gene insertion.

Soon after vector injection, Jesse developed a high fever of 40oC, and tachycardia, nausea, vomiting, muscular pain (3). Tests showed liver injury on the first day itself (4), and Jesse went into a coma after 2 days (5), developing acute respiratory distress syndrome (ARDS) requiring artificial ventilation (3). His organs started failing on the 3rd day and he was taken off life support on the 4th day. He died on September 17, 1999.

Ib. Jesse’s autopsy results: confounding factors suggesting another viral infection
Autopsy showed very large numbers of virus in spleen, lymph nodes and bone marrow (6), suggesting systemic virus spread triggered systemic inflammation leading to organ failure.

Jesse’s autopsy also showed that his bone marrow was depleted of erythroid precursor blood cells (6), something that couldn’t have happened overnight.

There was also abnormal maturation of precursor leukocyte lines (4) suggesting that Jesse likely had another ongoing infection, likely a parvovirus type B19 (5), when injected with the adeno (6).

Ic. What happened? Apparently several protocol violations.
What’s a safe virus dose for gene therapy? Did Jesse get too much virus, levels that would have inevitably provoked its well-known toxic side-effects (1)? Dose emerged as a major factor needing optimizing in gene therapy.

Another source of confusion regarding cause became the virus vector used which upon examination turned out to have duplicate sequences not engineered in the original virus vector (7). No one seems to know why or how this happened. Costlier long-term follow ups of viral vectors thus became necessary in future studies.

Jesse had high levels of blood ammonia when admitted to hospital, higher than the study cutoff level (6). Researchers injected drugs to lower his blood ammonia and proceeded with the study anyway. FDA determined this broke the rules of conduct.

Subsequent investigations uncovered that adverse side effects hadn’t been reported. Another patient in the study of 18 patients had suffered severe liver damage (8) before Gelsinger got his injection, and some monkeys who’d received similar, not the same, Rx, had died but no one at the NIH RAC (Recombinant DNA Advisory Committee) was ever informed about these serious adverse events.

The original protocol proposed injection into a distant blood vessel to minimize liver trauma. Direct injection into the hepatic artery, a major protocol change, was never approved by the the NIH RAC, which is supposed to approve all human recombinant DNA experiments before they begin, another protocol violation. Route emerged as a major factor needing optimizing in gene therapy.

Id. Who to recruit in gene therapy clinical trials?
Until Jesse, human gene therapy studies had mostly chosen terminally ill patients with no other chance of survival.

The OTC study was designed to help new-born OTC patients, i.e., originally the protocol was intended for dying babies with no other options (1). However, the IRB (Institutional Review Board) that examined it rejected it on the grounds that it was unreasonable to expect parents to give informed consent with their babies’ lives in such danger (1). Thus, this Penn study became the first to try such a high-risk procedure on a relatively healthy person such as Jesse.

Ie. Why so much confusion?
Confusion regarding regulatory oversight. Not just FDA but also NIH, specifically its RAC. Obviously, crucial information, and checks and balances fell through the cracks due to this strange dual regulatory system. Jesse’s death revealed crucial regulatory oversight gaps, gaps that then needed filling to restore confidence in gene therapy.

II. French SCID gene therapy: Inappropriate viral vector could cause cancer
Just one year after the Jesse Gelsinger tragedy, French scientists reported successful treatment of two SCID-XI children (9). The severity of their immunodeficiency means that SCIDs need to live in an extremely isolated environment.

Scientists injected a different virus vector, MoMLV (Moloney murine leukemia virus), carrying the curative gene (Gamma chain cytokine receptor subunit), into the patients’ lymphocytes. Unlike adeno, MoMLV, a retrovirus, directly integrates its genetic material into the host cell DNA.

They expanded these cells in vitro through cell culture, then injected them back into the patients. Both patients survived and could lead normal lives. Several other patients were subsequently treated and also cured.

Unfortunately, of the ~11 early patients treated with the MoMLV vector, 3 developed leukemia directly as a result of the gene transfer procedure (10). In all these patients the MoMLV vector had apparently integrated specifically near the LM02 (LIM domain only) gene, activating it and setting the leukemia in motion.

This leukemia result meant that gene therapy was just not ready for prime time yet since scientists needed to go back to the drawing board and develop safer virus vectors.

Gene therapy’s nuclear winter during the 2000s
As a result of these tragedies and in stark contrast to the 1990s when some early successes inculcated unrealistic expectations, the 2000s became a ‘lost decade’ for gene therapy (11). The ramifications included a chilling effect. Many researchers left the gene therapy field and funding dried up, both in academia and in industry. This tragic history now means greater regulatory burden, fewer researchers who stuck it out, and longer timelines towards Rx, all factors that drive up cost.

Gene therapy’s slow but steady comeback
2008 till date show a steady drumroll of modest successes for congenital eye diseases (12, 13), hereditary immune system disorders (14, 15, 16), cancer (17, 18, 19), and hemophilia B (20, 21).

Gene Therapy product approvals
In China: In 2003, SiBono Gene Tech Co.’s Gendicine™, a non-replicative adenoviral vector with the E1 gene replaced by a human p53 cDNA, approved for head-and-neck squamous cell carcinoma (22, 23). Approved by China’s State Food and Drug Administration (SFDA) (24), efficacy of this Rx has been questioned (24, 25), not a good portent for gene therapy for cancer. Two years later, SFDA approved Oncorine™, a conditionally replicative adenovirus developed by Sunway Biotech Co., for late-stage refractory nasopahyngeal cancer (26).
In the EU: In 2012, the EU approved UniQure’s Glybera for lipoprotein lipase deficiency (LPLD) (27). LPLD prevents the body from processing dietary fat.

At this point it’s appropriate to look at a brief history of gene therapy’s 1999-2000 lows (in orange) and more recent highs (in blue, see figure below from 28).

Commercial prospects for gene therapy circa 2015 look quite promising (see figures below from 29).


  • Dutch company whose main product, Glybera, its LPLD gene therapy Rx, was approved in 2012 in the EU.
  • Phase II trials ongoing in the US.
  • Also working on hemophilia and congestive heart failure, but only in Phase I at present.
  • Building a large production facility in Massachusetts for viral gene therapy Rx manufacture.
  • Funding: €44.5 million from Collier Capital, Glide Healthcare, Forbion, Chisesi Farmaceutici, the last involved in drug commercialization and marketing.:
    • February 2014: IPO raises $91.5 million.
    • Listed on the US NASDAQ.

Bluebird Bio

  • Works on adrenoleukodystrophy (ALD, a degenerative nervous system disease), blood diseases such as beta-thalassemia, where defective hemoglobin necessitates regular blood transfusions, and sickle cell, and cancer.
  • The ALD Rx is furthest along, in Phase II/III.
  • June 2013: IPO raises $116 million.
  • Also raised $134 million from research institutions, grants and venture capital.
  • Third Rock Ventures currently owns 28.9% of the company.

Xenon Pharmaceuticals

  • Two-tier strategy.
      • Work solo on orphan diseases.
      • Partner with big pharma on more common diseases.
    • Has licensing agreements with Genentech, Teva, Merck.
  • The Teva partnership for osteoarthritis is most advanced (Phase II clinical trials).
  • Also has a stake in UniQure.
  • Has raised $265 in funding.
  • November 2014: IPO raises $36 million.

Voyager Therapeutics

  • Started by Third Rock Ventures in February 2014, and managed by Mark Levin, one of Third Rocks’ co-founders.
  • $45 million investment.
  • Unlike other startups, Voyager has a group of highly experienced researchers who’ve
    • Worked on CNS disorders for years.
    • Have specialized knowledge of AAVs (Adeno-associated viruses), a safer alternative to adeno.

Crucial gene therapy questions
A. Why use viral vectors? Necessary evil for efficient gene delivery into cells until something better and safer comes along.
Genes can be delivered into cells by non-viral means. For e.g., liposomes (30, see figure below). Problem is cell uptake efficiency is very low, and gene expression is also transient (30, see figure below). By improving cell entry and expression, viral vectors as gene delivery vehicles could overcome such seemingly insurmountable problems. Of course, in hindsight their risks are also considerable, ranging from death to cancer.

B. Is a gene therapy cure permanent or rendered temporary by viral vector-induced immune responses?
Other issues that remained woefully under-studied until Jesse’s death were the viral vector-induced immune responses. As we saw with Jesse, these could be excessive and unsurprisingly, adenovirus has fallen out of favor as a gene delivery vehicle. However, even the newer vectors cannot guarantee no immune response, and another problem with immune responses is they could kick out the vectors hence eliminating gene expression, rendering the cure temporary, not permanent. Thus the promise of cure from viral vector gene therapy is not so clear-cut.

Potential for immune responses throws doubt on gene therapy promises of cure. This means that one-time Rx may not really withstand scrutiny in every single instance. Viral vector, dose, tissue target, injection route, these are but some of the key factors determining possibility, strength and duration of potential immune responses, responses that could eliminate the viral vector and its curative genetic cargo.

OTOH, cure from one time Rx is far more realistic with CRISPR/Cas9. However this technology is years away from commercialization. Currently there are 3 companies working on CRISPR/Cas9 for gene therapy, Editas Medicine, Intelia, and CRISPR Therapeutics. None of these companies have a disease focus as of yet but are at the earliest stage of technology development.

C. Gene therapy costs cannot be one size fits all.
Current estimated costs for genetic disease Rx are quite astronomical. These are lifelong Rx, not cures.

Hemophilia requires weekly prophylactic clotting factor Rx, estimated to cost $300,000 per year (31). Osteoarthritis costs ~$6000 (including insurer cost) per person annually in the US (32). Lifetime cost for sickle cell is ~$460,151 (33) while average annual cost for ALS is ~$63,692 (34, 35).

OTOH, gene therapy is the only way to treat genetic diseases permanently, at least in theory. However, even here, IPOs indicate that companies with products closer to commercialization, i.e., in Phase III or later, did better. In other words, the market for gene therapy has low risk tolerance, perhaps a lingering effect of its tragic and tangled history (see figure below from 29).

Among current gene therapy companies, UniQure is one of the few with an approved product, Glybera for LPLD. With a potential total of a mere 150 to 200 patients in Europe, UniQure is offering full course Glybera Rx in Germany for ~$1.35 million (36).

For diseases that affect such a tiny proportion of the population, any Rx that promises cure is already the best that they could hope for since small population numbers deter multiple commercial entities from investing in R&D for multiple Rx or cures. A captive market, in short.

Situation is different with diseases with a much larger population base, such as hemophilia and sickle cell. Multiple public and private entities are actively researching multiple Rx and/or cures so a large ticket price is less likely to be tolerated.

This is where governments, insurers and patient lobbies are likely to step in and develop newer approaches such as payment plans rather than one-time payment (29, 37, 38).


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