Trials to treatments: gene therapy

Will gene therapy treatments be available in my lifetime? And what are the barriers to making them a reality? We take a look at how far this technique has come.

Dr Beckie Port
Jun 11, 2018 · 9 min read

Gene therapy, a technique first described in 1972, works by using genes as a treatment. The idea is to provide the genetic instructions cells need to change their fate — this could be by replacing a faulty gene with a functional one or providing the instructions the cell needs to make certain protective factors.

However, getting the lab-made DNA inside nerve cells is tricky. Right now, the most effective way of putting DNA into a cell is to ‘hijack’ a virus. Some viruses are very good at infecting a cell by getting inside and inserting their own DNA into the DNA already in the cell. This can cause the cells to stop working or even die.

Scientists have found a way to re-programme viruses by removing the part of the DNA that allows them to reproduce and cause disease — making them harmless. The trick is to let them keep the ability to infect a cell. They can then be used as a carrier to take the genetic instructions into the cell, where they are needed.

While there has been active research in this area for around 45 years, gene therapy is, for the most part, still being developed. Treatments using this technique have rarely made it past the clinical trial stages, although it has promise for the treatment of a number of conditions — including inherited disorders like cystic fibrosis, some types of cancer, and certain viral infections.

The answer is yes, but not many. Previous approval of a gene therapy for a rare disease called lipoprotein lipase deficiency, granted by the EMA in 2012, has since been withdrawn. And a second example of a currently approved gene therapy involves using the technique on blood stem cells outside the body before transplanting them. The treatment, Strimvelis, is available in the UK for a rare immunodeficiency disease (ADA-SCID). The decision for the NHS to fund this treatment made the headlines last year.

Because of the risks involved, and the further research needed to ensure it is safe and effective, gene therapy is mainly being studied for conditions that do not have effective treatments. However, in over a decade of gene therapy trials for Parkinson’s there is a strong safety record of using this technique inside the body.

People with Parkinson’s don’t have enough of the chemical dopamine as nerve cells in a specific part of the brain, called the substantia nigra, have died. Current treatments replace the dopamine but can have side effects as the treatments are not able to target specific areas of the brain. But genes that increase the production of dopamine could help to alleviate the symptoms of the condition, potentially with fewer side effects, by targeting only the areas of the brain that are lacking in dopamine.

This was the idea behind the first gene therapy for Parkinson’s to make it through to clinical testing in the UK. ProSavin (also called OXB-101), developed by UK based biopharmaceutical company Oxford BioMedica, contains 3 genes which are vital for making dopamine (called TH, AADC and GCH1). In the early stage (phase I/II) clinical trials, which were carried out at the start of this decade, ProSavin was injected into the area of the brain lacking dopamine to help the remaining cells to increase their ability to produce the chemical.

At the time, the trial was a huge step forward in advanced gene-based treatment. Enhancements were made possible by a new infusion technique, which required fewer needles to be placed into the brain to deliver the treatment to those taking part.

In 2011, the Daily Mail featured some of the earliest results from the phase I study, which were presented at a conference:

“Some [of the participants] were able to take the bus or complete a round of golf for the first time in years.”

Published results of the phase I study supported the excitement shown by the Daily Mail. And patient diaries and quality of life measures also highlighted that, in addition to improvements in movement assessments, the participants were also seeing improvements in their every day life. However, expectations needed to be tempered against the realities that this was still an early stage trial and longer, larger and placebo controlled studies were needed to prove the treatment was safe and effective.

The ProSavin study continued into phase II, recruiting a further 6 participants, and promising, albeit modest effects, were published in 2014. Researchers reported an improvement in motor symptoms in all of those receiving the therapy 12 months following treatment. And in some participants the effect lasted for up to 48 months after ProSavin was administered.

The trial is ongoing as participants are taking part in long term follow up assessments. But, while this has been going on, Oxford BioMedica have been working on a second generation gene therapy.

The latest announcement from Oxford BioMedica relates a therapy called OXB-102 (now called AXO–LENTI–PD, since transfer to biotech company Axovant Sciences). On their website, the therapy is described as being…

“…designed to provide patient benefit for a number of years following a single administration.”

Like ProSavin, it works by introducing genes improve dopamine production. It is injected directly into the brain with the aim to improve the symptoms of Parkinson’s. The difference is the virus being used to get those genes into the cells — which now involved Oxford BioMedica’s own LentiVector® technology.

Phase I trials of OXB-102 are currently underway and recruiting people with Parkinson’s to take part, UK sites are at Cambridge University Hospital and UCL’s Queen’s Square Institute of Neurology in London.

While ProSavin was the first gene therapy to be trialled in the UK, it wasn’t the first gene therapy trial for Parkinson’s. Earlier trials included:

  • Trials of a gene therapy, called NLX-P101, which introduced the gene GAD to brain cells. The therapy was designed to even out signalling in the basal ganglia, the circuit in the brain that controls movement. The phase I study started in 2003 and was the first gene therapy trial for Parkinson’s. While the results from the phase II study were reported positively, suggesting the therapy may be able to reduce motor symptoms, research into NLX-P101 has since stalled.
  • Trials of just one of the components of ProSavin, the AADC gene. This therapy aimed to increase the amount of the protein that converts levodopa to dopamine — the 1-amino acid decarboxylase (AADC) protein — in brain cells. It is believed this could make levodopa therapy more effective. You can read more about how levodopa medications work in this previous blog post. The phase I clinical trial, which started in 2004, showed positive results for safety and some evidence that the therapy may improve symptoms. And a later revised phase I trial in 2007 also highlighted potential benefits that warrant further investigation.

Research is still ongoing on the benefit of an AADC gene therapy, although the mechanism for getting the AADC gene into the brain cells in some of the latest trials has changed.

The AADC gene therapy trials at the most advanced stages are being carried out by Voyager Therapeutics. A phase I study of their VY-AADC therapy has suggested that the treatment was safe and a single administration of was sufficient to increase AADC protein activity and the effectiveness of levodopa treatment. Results also suggest some some improvements in motor symptoms. The positive results so far have led to the FDA clearing a phase II/III study of VY-AADC, which is expected to start at multiple sites in the US later this year.

While therapies that alleviate symptoms with fewer side effects are highly sought after, the idea that gene therapy could help protect dopamine-producing brain cells has always been a valuable prize. By targeting the underlying causes, rather than masking symptoms this type of treatment could be the answer to slowing or even reversing the course of the condition.

The CERE-120 phase I trial was the first trial into a gene therapy of a protective factor for Parkinson’s and started in 2005. The aim was to deliver the gene coding for the protein Neurturin, which belongs to the GDNF family of proteins, to an area of the brain known as the putamen. While the phase I study suggested the therapy was safe, results from the later phase II study were mixed.

Undeterred, efforts were made to direct the treatment to further areas of the brain, this time directing the treatment towards the putamen and the substantia nigra. Again the phase I study was positive. However, the phase II study results, which were first announced in 2013, were disappointing. After 12 months, those receiving active treatment did not demonstrate improvements in the movement assessments when compared to the placebo group. The programme has since been suspended.

But CERE-120 isn’t the only example clinical gene therapy trial of a protective factor. A 5 year phase I trial of AAV2-GDNF, which aims to deliver GDNF to brain cells in the putamen, kicked off in 2013. This trial is still active but not recruiting and we look forward to seeing the results.

Progress is being at all stages of the research pipeline. While some treatments have yet to make it to clinical trials, there is much work developing gene therapies that may one day alleviate symptoms or slow the progression of Parkinson’s. There have also been huge improvements in technology which could allow more targeted and safer delivery of drugs to the brain.

But one question remains — if these treatments do make it to clinical trials, will the clinical trials be able to demonstrate that the treatment is working? Recent gene therapy trials in Parkinson’s have demonstrated that the technique appears to be safe, at least in the short to medium term but have consistently failed to demonstrate substantial improvements. And this problem is not unique to gene therapy trials. Researchers are coming to the conclusion that it may not be the treatment that doesn’t work, but the way we test it.

The difficulties come from the fact that we cannot accurately measure Parkinson’s and we may not be testing treatments in those who will actually benefit. But, through an ambitious collaboration, Parkinson’s UK are attempting to change that. You can read more about we’re improving clinical trials in a previous post.

It could be a race against time to develop better measures to assess Parkinson’s, and to improve clinical trials so that therapies in development can finally make it to the people who need them.

The Parkinson’s UK research blog is completely free but we can only continue to produce content with the support of people like you. You can help our vital work to bring forward better treatments and a cure, and improve quality of life for everyone affected by Parkinson’s. Support us in a way that suits you with a regular contribution or a single donation that rewards the posts you enjoy most.

Parkinson’s UK

Get the latest research news, discover more about Parkinson’s and read about how others are getting involved. For information and support, visit

Dr Beckie Port

Written by

Research Communications Manager at @ParkinsonsUK. Ex-researcher in oncology and virology.

Parkinson’s UK

Get the latest research news, discover more about Parkinson’s and read about how others are getting involved. For information and support, visit

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