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Gene Therapy for Dementia - Research & Industry Pipelines.

Given that this week is the Alzhemier's Society UK Action Week, it got me thinking about the actions we - as in industry and research - are taking towards finding cures for the causes of dementia.

Lately, with the work we here at Cellix have been doing, I've been looking a lot into the fascinating field of the potential applications of gene editing. With the juggernaut that is CRISPR, it seems that there is no limit to what gene editing can do - that is, in theory.

The reality, as always, is somewhat more complicated. Despite years of investment, history has shown us that diseases causing dementia have typically been difficult to develop drugs for.

So my question became; where are we in terms of gene therapy for these diseases now?


Dementia is a group of symptoms which have touched the lives of many, and has several disease causes. Symptoms can include psychological and cognitive changes, including memory loss, difficulty in communication and cognitive functioning, confusion, personality changes and hallucinations (source: Mayo Clinic).

Causes of dementia include Alzheimer's disease, Huntington's, Parkinson's, vascular dementia, Lewy body dementia and frontotemporal dementia among others.

Currently, there are no therapies which the reverse these diseases entirely, though drugs to halt their progression have improved hugely.

Not all diseases causing dementia are suitable to target using gene therapy - for example, vascular dementia (a result of damage brain blood vessels). While some diseases are associated with a higher incidence of vascular dementia, it's disparate causes make it difficult to target with gene therapy.

However, some other causes of dementia are viable targets for gene therapy. Many diseases causing dementia have the common theme of protein aggregation as a result of misfolding - these include Alzheimer's, Parkinson's, Huntington's, and some prion diseases such as Creutzfeldt-Jakob disease.

Gene therapies for these diseases typically aim to prevent this protein misfolding or aggregation, and are often delivered to the brain using modified viruses.


Alzheimer's is the most common cause of dementia. It is a type of tauopathy - an accumulation of tau proteins. Currently there are 5 FDA-approved drugs for Alzheimer's patients - but these tackle symptoms where we want a cure.

Alzheimer's Disorder

Image: abnormal proteins in the brain cause neurological symptoms. Source: BrightFocus Foundation.

Industry has had a few knocks in this field; so far, 99.6% of Alzheimer's drugs that have made it to late-stage clinical trials have so far failed. Gene therapy may offer the inroads the pharma companies desire.

This is beginning to be reflected in investment. Johnson & Johnson, a titan in pharma, has formed an Alzheimer's gene therapy research pact with the University of Pennsylvania; AbbVie and Voyager are collaborating to produce antibody-based gene therapies; and both New York-based Vybion and Paris-based BrainVectis are working on gene therapies with applications for both Huntington's and Alzheimer's. Sangamo Therapeutics is investigating gene regulation to reduce the levels of tau, a crucial protein in Alzheimer's.

In addition to the pharma industry investing in these drugs, basic research continues to move forward; there are now over 3,000 articles on PubMed about gene therapy in Alzheimer's disease.

Identification of potential new targets also progresses: researchers at Imperial College London in 2016 used a modified lentivirus to deliver the gene PGC-1 to the brain. In mouse models after 4 months, this group did better than their untreated counterparts.


Huntington's disease is a progressive, rare, fatal neurodegenerative disorder that causes dementia in the young adults who are diagnosed with it. It is caused by mutant repeats in a DNA sequence at the tail end of the huntingtin protein gene.

uniQure are developing a gene therapy called AMT-130 or Huntington's and have released data showing that in an animal model, there were reductions in the mutant huntingtin profile in the treated cohort. uniQure have already received orphan drug status from the European Medicines Agency and stated they expect to file for investigational new drug (IND) status in 2018, hoping to become the first AAV to enter clinical development for Huntington's.

This is only one example from pharma. US company Ionis have also been working on Huntington's, with an antisense oligonucleotide treatment which has gone to human trial. Sanofi were working with Voyager for experimental treatments for Huntington's.

The research community around Huntington's is also extensive, and has embraced the advances making gene therapy possible. In February 2018, Polish researchers published in Frontiers in Neuroscience demonstrating their improved CRISPR-Cas9 system for working towards a treatment, with a more specific Cas9 nuclease than previously.

Parkinson's and Dementia with Lewy Bodies

Lewy Body Dementias are progressive dementias accountable for up to 25% of all dementia, characterised by the build up of 'Lewy bodies' in the brain. Parkinson's presents first as a movement disorder but in later stages is associated with dementia which is also associated with Lewy body build up whereas Dementia with Lewy Bodies presents first as a memory disorder. It can be difficult to distinguish the two.

Research trends in Parkinson's treatment include targeting protein aggregation, altering the production of neurotransmitters, and using growth factors to regenerate damaged tissue.

Industry is also investing; Massachusetts-based Voyager is working on a gene therapy to restore the ability of the brain to produce dopamine. The New York-based Prevail raised $75 million dollars this year for a gene therapy for aggressive Parkinson's; Edinburgh-based Synpromics are working on a gene therapy for Parkinson's focusing on controlling therapeutic gene expression. San Diego-based Ceregene are working on gene therapy to restore injured dopamine-producing neurons.


Other causes of dementia lag behind in terms of scale of research effects but progress is still being made; in Alabama, researchers have used an adeno-associated virus to add a functional copy of the defective gene associated with frontotemporal dementia. In a mouse model, this approach showed promise, stopping the build up of waste fat (lipofuscin), which damages cells.


Diseases causing dementia are complex and may have multiple factors influencing their onset and progression. This causes challenges to the researchers who wish to develop treatments for them; as do other factors such as inaccurate models and difficulties in drug delivery.

Gene therapy-specific challenges include ensuring long-term gene expression, and preventing off target transduction or transgene expression.

Despite this, approaches using gene therapy are increasingly strong contenders for an effective cure for patients of suitable target diseases, due to improved targeting, delivery and gene expression.

While none of these treatments are currently available on the market, research frontiers continue to be pushed and further awareness, investment and research will help reach the goal of developing curative therapies for patients.

Dementia Action Week is driven by the Alzheimer's Society.

For more information visit their site or join in the conversation #DAW2018

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