Gene therapy: Ingenious; Fixing a body’s broken genes is becoming possible

Gene therapy: Ingenious; Fixing a body’s broken genes is becoming possible

Feb 8th 2014 | New York | From the print edition


IT SOUNDS like science fiction, and for years it seemed as though it was just that: fiction. But the idea of gene therapy—introducing copies of healthy genes into people who lack them, to treat disease—is at last looking as if it may become science fact.

The field got off to a bad start, with the widely reported death of an American liver patient in 1999. In 2003 some French children who were being treated with it for an immune-system problem called SCID developed leukaemia. Since then, though, things have improved. Indeed one procedure, for lipoprotein lipase deficiency (which causes high levels of blood fats, with all the problems those can bring), has been approved, in Europe, for clinical use.

The most recent success, announced last month in theLancet, was of an experimental treatment for choroideremia, a type of blindness. This is caused by mutation of the gene for a protein called REP1. Without REP1, the eye’s light receptors degenerate. Robert MacLaren of Oxford University used a virus to deliver working versions of the REP1 gene to the most light-sensitive part of the retina. Five of the six participants in the trial duly experienced an improvement in their sensitivity to light. Two were so improved that they could read more letters than previously on a standard eye chart.

Dr MacLaren’s work complements that of Albert Maguire and Jean Bennett at the University of Pennsylvania, who use gene therapy to treat another eye disease, Leber’s congenital amaurosis. A defective version of a gene called RPE65 means that, in this condition, retinal cells are starved of vitamin A, which also causes blindness. Putting normal copies of RPE65 into the retina leads, as with REP1, to greater light sensitivity and—sometimes—clearer vision.

Drs MacLaren, Maguire and Bennett all use adeno-associated viruses (a type not known to cause illness, and which does not much provoke the immune system) to carry their genetic payloads to the target. Luigi Naldini of the San Raffaele Telethon Institute for Gene Therapy, in Milan, employs a rather scarier vector—one derived from HIV, the virus that causes AIDS—because its life cycle involves it integrating its genes into its host cells’ nuclei.

Last year Dr Naldini and his colleagues reported that, using their safely neutered version of HIV, they had inserted working copies of genes into blood stem cells which lack them, in order to treat metachromatic leukodystrophy (which damages nerves) and Wiskott-Aldrich syndrome (which harms the immune system and reduces blood’s ability to clot). In both cases—though in only a handful of patients, for the diseases are rare—Dr Naldini’s approach either prevented the disease or at least halted its progress.

The rarity of metachromatic leukodystrophy, Wiskott-Aldrich syndrome and many other diseases for which gene therapy might be appropriate means a lot of the applications of this approach are narrow. But a different one—constructing tailored genes and using them to guide the immune system—may have wider application, specifically against cancer.

Michel Sadelain, of the Memorial Sloan-Kettering Cancer Centre, in New York, is one of those at the forefront of a method that works this way. It employs chimeric antigen receptor (CAR) cells, which are engineered versions of T-cells, the part of the immune system that kills body cells, including tumorous ones, which have become threats.

Dr Sadelain’s trick is to take natural T-cells from patients (specifically, leukaemia and lymphoma patients) and add to them genes which turn those cells’ attention to the tumour in question, causing them to seek out its cells and destroy them. He then returns the modified cells to the patient, where they multiply and attack.

The CAR pool

The extra genes in CAR cells are derived in part from monoclonal-antibody genes. These have, in turn, been selected for their affinity to the target tumour. Because CAR cells multiply in the body this is, as Dr Sadelain puts it, like creating a living drug.

Last year Dr Sadelain’s team, and also another group led by Carl June at the University of Pennsylvania, published results showing the promise of CAR cells in treating people with acute lymphoblastic leukaemia. Dr Sadelain’s paper showed that they caused full remission in all five adult patients treated (though two subsequently died of complications, one set of which was unrelated to the treatment); Dr June’s, that they eradicated the cancer from two children. And, at a meeting of the American Society of Hematology held in December, both researchers reported further successes.

There is, moreover, one further technique that might bring gene therapy into the mainstream. Current approaches work by adding genes to affected cells. But it may be possible to modify those cells’ existing, broken genes, using a method called CRISPR-Cas9 editing, a process that takes advantage of a natural antiviral system which chops up genetic material.

CRISPR-Cas9 editing is specific to particular sequences of genetic letters, and can thus be tweaked to do a researcher’s bidding. In a recent edition of Cell, Sha Jiahao of Nanjing Medical University showed how to use it to execute the reverse of gene therapy—creating genetic problems, rather than solving them—in monkeys. His aim was to produce model organisms that might help understanding of diseases in human beings (though making such models out of monkeys is controversial). But the technique might eventually be employed to do running repairs on damaged DNA in people.

That, if it ever happens, is a long way off. In the meantime, the promise of gene therapy can be seen in the fact that it is attracting lawyers. The University of Pennsylvania has licensed its CAR technology to Novartis, a Swiss drugs firm. The pair of them are now fending off a lawsuit brought by competitors including Juno Therapeutics, the creation of three research centres of which Memorial Sloan-Kettering is one. For patients, that suggests gene therapy really is something worth fighting over.


About bambooinnovator
Kee Koon Boon (“KB”) is the co-founder and director of HERO Investment Management which provides specialized fund management and investment advisory services to the ARCHEA Asia HERO Innovators Fund (, the only Asian SMID-cap tech-focused fund in the industry. KB is an internationally featured investor rooted in the principles of value investing for over a decade as a fund manager and analyst in the Asian capital markets who started his career at a boutique hedge fund in Singapore where he was with the firm since 2002 and was also part of the core investment committee in significantly outperforming the index in the 10-year-plus-old flagship Asian fund. He was also the portfolio manager for Asia-Pacific equities at Korea’s largest mutual fund company. Prior to setting up the H.E.R.O. Innovators Fund, KB was the Chief Investment Officer & CEO of a Singapore Registered Fund Management Company (RFMC) where he is responsible for listed Asian equity investments. KB had taught accounting at the Singapore Management University (SMU) as a faculty member and also pioneered the 15-week course on Accounting Fraud in Asia as an official module at SMU. KB remains grateful and honored to be invited by Singapore’s financial regulator Monetary Authority of Singapore (MAS) to present to their top management team about implementing a world’s first fact-based forward-looking fraud detection framework to bring about benefits for the capital markets in Singapore and for the public and investment community. KB also served the community in sharing his insights in writing articles about value investing and corporate governance in the media that include Business Times, Straits Times, Jakarta Post, Manual of Ideas, Investopedia, TedXWallStreet. He had also presented in top investment, banking and finance conferences in America, Italy, Sydney, Cape Town, HK, China. He has trained CEOs, entrepreneurs, CFOs, management executives in business strategy & business model innovation in Singapore, HK and China.

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