Improving Gene Therapy
In December 2023, the FDA made history by approving the first human gene therapy for sickle cell disease. This was quite a revolution and opened the way for much more gene therapy for other incurable diseases.
One difficulty in all gene therapy procedures is getting enough of the intended genetic material delivered into the target cells. This can cause multiple issues, from too low gene modification to be efficient as a medicine to un-targeted cells being modified or immune reactions and side effects from too concentrated a dose. And, of course, using more than needed gene editing medicine is expensive.
Luckily, researchers might have found a way to solve this issue, using electric pulses to boost the efficiency of gene transformation 40 times.
Electricity For Gene Editing
Using electricity for gene modification is not really a new concept in itself, with electroporation a very ancient method used to create GMOs. However, in the case of this method, the damage inflicted on the cells by the very high voltage makes it only fit for modifying cell culture, bacteria, or plants, and not the gene inside a living animal or human.
Source: Thermo Fisher
What the researchers at the University of Wisconsin–Madison have discovered is that gene therapies can be improved with a short pulse of electricity instead. This was done in collaboration between University of Wisconsin–Madison researchers ( Susan Hagness and John Booske and PhD student Yizhou Yao) and Hans Sollinger, a world-renowned transplant surgeon.
Source: University of Wisconsin-Madison
Contrary to the more brutal electroporation method, the electric pulses are very quick, only 80 milliseconds long. They allow for targeting only specific cells. Thanks to mico-electrodes inserted surgically for the duration of the treatment, gene therapy could mostly affect only the organ and cells treated with electricity.
“What we started talking about was local, targeted delivery and whether there was a way of getting the treatment DNA directly into the liver without passing it through the entire body and triggering the immune system.
And whether we could use electric pulses in order to make this delivery process more efficient and dramatically reduce the dose needed.” – Pr. Susan Hagness
Curing Diabetes With Electric Gene Therapy?
Many new gene therapies rely on CRISPR, a new gene editing tool allowing for the modification of existing genes in a very controlled fashion, often changing just one genetic base. But for the insertion of an entire gene, it is often as good, if not better, to use viral vectors.
This is what the researchers are looking to do: inserting into human liver cells the gene responsible for the production of insulin. By doing so, they could repair the insulin-producing function in Type-1 diabetes patients. This would result in the patient”s liver, instead of his pancreas producing the needed insulin.
In order to test if electricity could boost genetic transformation, they used a gene coding for a fluorescent protein. If the cell is transformed and carries the new gene, it will appear fluorescent in a dedicated microscope.
Source: PLOS
When using the viral vector alone (“b”), only a small percentage of the liver cells were transformed, a well-known issue preventing this sort of therapy from being medically useful.
However, when exposed to the electric pulse (“c”), 40x more cells had incorporated the new genetic material.
In theory, the method could then be adapted to transfer not a gene for a fluorescent protein but a gene for insulin production.
The Next Steps
The next steps must confirm whether the improved transformation can be adapted into an actual medical protocol.
This proof of concept was done on cultured cells in a petri dish. So, proving that it also works in a full liver and in a live animal model will be needed. In the same way, further down the road, it will need to be proven that this is safe enough to use on a human live liver.
Source: PLOS
Another thing will be to test if the transformation of the liver cell leads to a durable, stable, and self-regulated production of insulin. Only then will it be able to become a good candidate for curing Type-1 diabetes.
Using different lengths and intensities of electric pulses and testing on other organs and cell types will also be useful in understanding if this can be done for cells and organs other than the liver.
Lastly, both researchers and regulatory authorities like the FDA will want to understand how the electric pulses work. It is known that electric pulses can open up micro gaps in a cell membrane. But the virus particles used are way bigger than these gaps. So it is not really clear what is happening, and why the virus is a lot more efficient at injecting the fluorescent protein gene thanks to the electric pulses.
Interestingly, it could also imply that there is an entirely different mechanism at play, one that researchers have been so far unaware of.
Gene Therapy Companies
The discovery of the efficiency of electric pulse in boosting viral-vector gene therapy could give a boost to this field. Lately, it has been a little overshadowed by the success of CRISPR-based therapy.
This was largely due to the low transformation efficiency of viral-based therapies.
With this issue potentially solved, virus-based gene therapies could make an unexpected comeback at the forefront of gene therapies’ potential miracle cures.
1. Voyager Therapeutics
This biotech startup specializes in Adeno-Associated Viruses (AAV) vector engineering. It is developing next-generation AAV capsids for gene therapies.
A key technology of the company is TRACER (Tropism Redirection of AAV by Cell-type-specific Expression of RNA), a platform allowing it to quickly discover new AAV “with robust penetration of the blood-brain barrier”.
This gives Voyager a strong advantage in gene therapies focused on the brain and nervous system, which are usually difficult to reach with traditional medicine and gene therapies.
Gene Therapy: direct injection (Intra-Parenchymal, Intra-Cerebro Ventricular, Intra-Thecal, Intra-Cisterna Magna) can result in patchy delivery, inadequate brain distribution, low transduction efficiencies, and safety concerns.
This focus boosted the company profile, with partnerships signed with several larger pharmaceutical companies, including Sangamo and Novartis. The Novartis collaboration and capsid license agreement was worth $1.3 bln with Voyager to develop gene therapies for Huntington’s disease and SMA. And the two Neurocrine Biosciences partnerships could yield as much as $5.5B if they reach all their milestones.
Source: Voyager
The company’s R&D pipeline is most advanced on Alzheimer’s disease, with other research programs on ALS, Huntington’s disease, Parkinson’s, Friedreich’s Ataxia, SMA, and prion disease.
Source: Voyager
Considering that the electric pulse gene therapy experiment used adeno-associated virus vectors (AAV8), it is reasonable to expect that improved efficiency could also work on Voyager’s AAV proprietary strains.
However, further testing on the safety of the micro electric pulses used would be needed, as most of Voyager potential therapies are targeting the nervous system.
2. Bluebird Bio
Together with CRISPR Therapeutics, Bluebird was a company granted approval in December 2023 for a gene therapy on sickle cell disease, under the commercial name Lyfgenia. The same therapy is also approved for beta-thalassemia, under the commercial name Zynteglo.
Lyfgenia didn’t make use of CRISPR. Instead, it went the traditional route of gene therapy treatment by utilizing a lentiviral vector (LVV), a family of viruses, to modify genes.
Here, the blood stem cells of SDC patients are genetically modified to produce a special hemoglobin HbAT87Q which functions much like any normal adult hemoglobin but is gene-therapy derived and delivered to the patient.
The company’s success in approval of Lyfgenia has not really translated into success for its stock price. However, the success of the company in getting 3 approved gene therapies using LVV is an indication of its expertise in using viruses for gene therapy.
It could be that electric pulses boosting efficiency 40 times and improving the targeting of gene therapy is the key to unlocking LVV for many more applications. The company is now going to get revenues from its $3.1M a piece Lygenia therapy and already has enough cash runway to last until 2026. So investors willing to take a chance might see the fortune of the company and its stock price turning.