Therapeutic focus – Gene therapy slowly rises from the ashes


Gene therapy, a groundbreaking concept whose inability to deliver on huge expectations was at least partly responsible for the 1999/2000 biotech boom and bust, is back on investors’ agenda.

Current hopes rest on several projects aiming to treat rare diseases – whose underlying basis in specific genetic mutations makes them a logical target for DNA therapeutics – and clinical trial readouts provide several important catalysts (see table below). What is more, in the past year cash has started flowing into the space again.

The poster child for this new wave of potential therapeutics is Uniqure’s Glybera, a treatment for lipoprotein lipase deficiency that last year became the first ever gene therapy to gain regulatory approval – albeit only in Europe.

Until then this was a field in which safety issues had scuppered initial hopes, in addition to delivery and immune response problems. The permanence of a treatment meant for instance that, in contrast to a drug, side effects could not be easily reversed.

While work using DNA to treat diseases has continued apace, cardiovascular and oncology indications are proving tough (Unequivocal failure sees Vical ditch gene therapy, August 13, 2013). Rather, in the latter it is through small-molecule and immune therapy approaches that most progress is being made.


Still, none of this detracts from the fact that in rare inherited disorders several gene therapy companies have secured large amounts of cash.

Uniqure itself completed a $92m float this month, though tellingly it chose Nasdaq and not an exchange in Europe, where it is based. Glybera has yet to be launched, and the cash will pay for a manufacturing plant as well as supporting its US development.

Another notable gene therapy business, Bluebird Bio, raised $116m in a Nasdaq IPO last June. Bluebird is working on the ex vivo insertion of functional gene copies into a patient's own hematopoietic stem cells, and its Lenti-D project, concerning the ABCD1 gene, is in a phase II/III study.

An ongoing earlier programme has shown the maintenance of safety and therapeutic benefits for more than five years. A related project, LentiGlobin, aims to treat beta-thalassemia and sickle cell disease by inserting a fully functional human beta-globin gene, and naturally all these studies involve very small numbers of patients.

Clinical-stage gene therapy projects for rare, inherited disorders*
Status Project Company Condition Trial IDs Patients (lead trial) Primary completion (lead trial)
Approved Glybera UniQure Familial lipoprotein lipase deficiency NCT01109498 14
Phase III AAV2-hRPE65v2  Spark Therapeutics Leber's congenital amaurosis NCT00999609
24 Apr 2015
Phase II/III Lenti-D  Bluebird Bio Childhood cerebral adrenoleukodystrophy NCT01896102 15 Aug 2018
Phase II AGTC-0106  Applied Genetic Technologies AAT congenital deficiency NCT01054339
9 Nov 2011
Phase I/II LCA2 Applied Genetic Technologies Leber's congenital amaurosis NCT00749957 12 Sep 2014
StarGen  Sanofi/Oxford BioMedica Stargardt disease NCT01367444
28 Nov 2014
UshStat Sanofi/Oxford BioMedica Retinitis pigmentosa/Usher syndrome NCT01505062
18 Jul 2016
AAV8-hFIX19 Spark Therapeutics Haemophilia B NCT01620801 15 Oct 2019
AskBio009  Asklepios BioPharmaceutical Haemophilia B NCT01687608 16 Nov 2019
LentiGlobin Bluebird Bio Thalassaemia NCT01745120 15 Jul 2017
Généthon Chronic granulomatous disease NCT01855685 20 Sep 2015
Haematopoietic stem cell therapy Généthon Wiskott-Aldrich syndrome NCT01347242
5 Dec 2013
SAF-301 Lysogene Sanfilippo syndrome NCT02053064 5 Jun 2014
Phase I AAV2-sFLT01  Sanofi Age-related macular degeneration NCT01024998 34 Jul 2014
RetinoStat Sanofi/Oxford BioMedica Age-related macular degeneration NCT01301443
18 Sep 2013
Neo-rhGAA Sanofi Pompe's disease NCT01898364 21 Apr 2015
*comprises only projects with studies listed in

Beyond Glybera the most advanced of these genetic disease assets is owned by the private company Spark Therapeutics, which is in phase III with an AAV vector delivering genetic material to correct mutations in the RPE65 gene.

Such mutations lie behind an inherited form of retinal degeneration called Leber's congenital amaurosis 2, and the trial should yield data next year. Spark, a spin-out of from The Children’s Hospital of Philadelphia, raised an impressive $50m in venture financing last October.

A gene therapy for another inherited form of blindness, choroideraemia, could enter phase III later this year. NightstaRx, an Oxford University spin-out, raised $20m in venture funding last month to run the trial (Syncona has the finishing line in sight with $20m gene therapy investment, January 31, 2014).

Big pharma?

Interestingly enough, rare disease gene therapy seems to be an area without much big company involvement; the exception is Sanofi’s deal with the UK’s Oxford Biomedica.

This alliance’s earlier key focus had been the cancer vaccine Trovax, but this failed in a phase II study in renal cancer. Undeterred, Oxford has ploughed on with gene therapy, where it still boldly states that it wants to become the world leader.

The UK group can still count on Sanofi as a partner in three projects: StarGen, UshStat and RetinoStat. Indeed, the French group this month broadened its rights to all ocular indications for the first two.

All three Sanofi-partnered products use LentiVector technology to deliver healthy copies of the ABCR, MYO7A, and endostatin and angiostatin genes respectively. StarGen and RetinoStat studies could read out this year.

Of course, nothing is plain sailing in gene therapy. One company, Applied Genetic Technologies, has taken two projects into phase II, with one set to yield data in Leber's congenital amaurosis 2 this year.

But the group now describes these as mere proof-of-concept programmes for its AAV vector-based approach, and has switched its focus to three other preclinical-stage ophthalmology projects. The private group Asklepios Biopharmaceutical also has an AAV technology, but beyond signing a cross-licence with Genzyme last year it has had little to shout about.

Nevertheless, in the current market companies must make hay while the sun shines, and perhaps realising this Applied Genetic Technologies filed last month for an IPO to raise up to $70m. Others could yet follow before the current funding window shuts.

To contact the writers of this story email Jacob Plieth or Joanne Fagg in London at or follow @JacobEPVantage and @JoEPVantage on Twitter

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