In a world first, we heard last week that US surgeons had transplanted a kidney from a gene-edited pig into a living human. News reports said the procedure was a breakthrough in xenotransplantation – when an organ, cells or tissues are transplanted from one species to another. https://www.youtube.com/embed/cisOFfBPZk0?wmode=transparent&start=0 The world’s first transplant of a gene-edited pig kidney into a live human was announced last week.

Champions of xenotransplantation regard it as the solution to organ shortages across the world. In December 2023, 1,445 people in Australia were on the waiting list for donor kidneys. In the United States, more than 89,000 are waiting for kidneys.

One biotech CEO says gene-edited pigs promise “an unlimited supply of transplantable organs”.

Not, everyone, though, is convinced transplanting animal organs into humans is really the answer to organ shortages, or even if it’s right to use organs from other animals this way.

There are two critical barriers to the procedure’s success: organ rejection and the transmission of animal viruses to recipients.

But in the past decade, a new platform and technique known as CRISPR/Cas9 – often shortened to CRISPR – has promised to mitigate these issues.

What is CRISPR?

CRISPR gene editing takes advantage of a system already found in nature. CRISPR’s “genetic scissors” evolved in bacteria and other microbes to help them fend off viruses. Their cellular machinery allows them to integrate and ultimately destroy viral DNA by cutting it.

In 2012, two teams of scientists discovered how to harness this bacterial immune system. This is made up of repeating arrays of DNA and associated proteins, known as “Cas” (CRISPR-associated) proteins.

When they used a particular Cas protein (Cas9) with a “guide RNA” made up of a singular molecule, they found they could program the CRISPR/Cas9 complex to break and repair DNA at precise locations as they desired. The system could even “knock in” new genes at the repair site.

In 2020, the two scientists leading these teams were awarded a Nobel prize for their work.

In the case of the latest xenotransplantation, CRISPR technology was used to edit 69 genes in the donor pig to inactivate viral genes, “humanise” the pig with human genes, and knock out harmful pig genes. https://www.youtube.com/embed/UKbrwPL3wXE?wmode=transparent&start=0 How does CRISPR work?

A busy time for gene-edited xenotransplantation

While CRISPR editing has brought new hope to the possibility of xenotransplantation, even recent trials show great caution is still warranted.

In 2022 and 2023, two patients with terminal heart diseases, who were ineligible for traditional heart transplants, were granted regulatory permission to receive a gene-edited pig heart. These pig hearts had ten genome edits to make them more suitable for transplanting into humans. However, both patients died within several weeks of the procedures.

Earlier this month, we heard a team of surgeons in China transplanted a gene-edited pig liver into a clinically dead man (with family consent). The liver functioned well up until the ten-day limit of the trial.

How is this latest example different?

The gene-edited pig kidney was transplanted into a relatively young, living, legally competent and consenting adult.

The total number of gene edits edits made to the donor pig is very high. The researchers report making 69 edits to inactivate viral genes, “humanise” the pig with human genes, and to knockout harmful pig genes.

Clearly, the race to transform these organs into viable products for transplantation is ramping up.

From biotech dream to clinical reality

Only a few months ago, CRISPR gene editing made its debut in mainstream medicine.

In November, drug regulators in the United Kingdom and US approved the world’s first CRISPR-based genome-editing therapy for human use – a treatment for life-threatening forms of sickle-cell disease.

The treatment, known as Casgevy, uses CRISPR/Cas-9 to edit the patient’s own blood (bone-marrow) stem cells. By disrupting the unhealthy gene that gives red blood cells their “sickle” shape, the aim is to produce red blood cells with a healthy spherical shape.

Although the treatment uses the patient’s own cells, the same underlying principle applies to recent clinical xenotransplants: unsuitable cellular materials may be edited to make them therapeutically beneficial in the patient.

We’ll be talking more about gene-editing

Medicine and gene technology regulators are increasingly asked to approve new experimental trials using gene editing and CRISPR.

However, neither xenotransplantation nor the therapeutic applications of this technology lead to changes to the genome that can be inherited.

For this to occur, CRISPR edits would need to be applied to the cells at the earliest stages of their life, such as to early-stage embryonic cells in vitro (in the lab).

In Australia, intentionally creating heritable alterations to the human genome is a criminal offence carrying 15 years’ imprisonment.

No jurisdiction in the world has laws that expressly permits heritable human genome editing. However, some countries lack specific regulations about the procedure.

Is this the future?

Even without creating inheritable gene changes, however, xenotransplantation using CRISPR is in its infancy.

For all the promise of the headlines, there is not yet one example of a stable xenotransplantation in a living human lasting beyond seven months.

While authorisation for this recent US transplant has been granted under the so-called “compassionate use” exemption, conventional clinical trials of pig-human xenotransplantation have yet to commence.

But the prospect of such trials would likely require significant improvements in current outcomes to gain regulatory approval in the US or elsewhere.

By the same token, regulatory approval of any “off-the-shelf” xenotransplantation organs, including gene-edited kidneys, would seem some way off.

Christopher Rudge, Law lecturer, University of Sydney

This article is republished from The Conversation under a Creative Commons license. Read the original article.

A recent study has suggested Shingrix, a relatively new vaccine given to protect older adults against shingles, may delay the onset of dementia.

This might seem like a bizarre link, but actually, research has previously shown an older version of the shingles vaccine, Zostavax, reduced the risk of dementia.

In this new study, published last week in the journal Nature Medicine, researchers from the United Kingdom found Shingrix delayed dementia onset by 17% compared with Zostavax.

So how did the researchers work this out, and how could a shingles vaccine affect dementia risk?

From Zostavax to Shingrix

Shingles is a viral infection caused by the varicella-zoster virus. It causes painful rashes, and affects older people in particular.

Previously, Zostavax was used to vaccinate against shingles. It was administered as a single shot and provided good protection for about five years.

Shingrix has been developed based on a newer vaccine technology, and is thought to offer stronger and longer-lasting protection. Given in two doses, it’s now the preferred option for shingles vaccination in Australia and elsewhere.

In November 2023, Shingrix replaced Zostavax on the National Immunisation Program, making it available for free to those at highest risk of complications from shingles. This includes all adults aged 65 and over, First Nations people aged 50 and older, and younger adults with certain medical conditions that affect their immune systems.

What the study found

Shingrix was approved by the US Food and Drugs Administration in October 2017. The researchers in the new study used the transition from Zostavax to Shingrix in the United States as an opportunity for research.

They selected 103,837 people who received Zostavax (between October 2014 and September 2017) and compared them with 103,837 people who received Shingrix (between November 2017 and October 2020).

By analysing data from electronic health records, they found people who received Shingrix had a 17% increase in “diagnosis-free time” during the follow-up period (up to six years after vaccination) compared with those who received Zostavax. This was equivalent to an average of 164 extra days without a dementia diagnosis.

The researchers also compared the shingles vaccines to other vaccines: influenza, and a combined vaccine for tetanus, diphtheria and pertussis. Shingrix and Zostavax performed around 14–27% better in lowering the risk of a dementia diagnosis, with Shingrix associated with a greater improvement.

The benefits of Shingrix in terms of dementia risk were significant for both sexes, but more pronounced for women. This is not entirely surprising, because we know women have a higher risk of developing dementia due to interplay of biological factors. These include being more sensitive to certain genetic mutations associated with dementia and hormonal differences.

Why the link?

The idea that vaccination against viral infection can lower the risk of dementia has been around for more than two decades. Associations have been observed between vaccines, such as those for diphtheria, tetanus, polio and influenza, and subsequent dementia risk.

Research has shown Zostavax vaccination can reduce the risk of developing dementia by 20% compared with people who are unvaccinated.

But it may not be that the vaccines themselves protect against dementia. Rather, it may be the resulting lack of viral infection creating this effect. Research indicates bacterial infections in the gut, as well as viral infections, are associated with a higher risk of dementia.

Notably, untreated infections with herpes simplex (herpes) virus – closely related to the varicella-zoster virus that causes shingles – can significantly increase the risk of developing dementia. Research has also shown shingles increases the risk of a later dementia diagnosis.

The mechanism is not entirely clear. But there are two potential pathways which may help us understand why infections could increase the risk of dementia.

First, certain molecules are produced when a baby is developing in the womb to help with the body’s development. These molecules have the potential to cause inflammation and accelerate ageing, so the production of these molecules is silenced around birth. However, viral infections such as shingles can reactivate the production of these molecules in adult life which could hypothetically lead to dementia.

Second, in Alzheimer’s disease, a specific protein called Amyloid-β go rogue and kill brain cells. Certain proteins produced by viruses such as COVID and bad gut bacteria have the potential to support Amyloid-β in its toxic form. In laboratory conditions, these proteins have been shown to accelerate the onset of dementia.

What does this all mean?

With an ageing population, the burden of dementia is only likely to become greater in the years to come. There’s a lot more we have to learn about the causes of the disease and what we can potentially do to prevent and treat it.

This new study has some limitations. For example, time without a diagnosis doesn’t necessarily mean time without disease. Some people may have underlying disease with delayed diagnosis.

This research indicates Shingrix could have a silent benefit, but it’s too early to suggest we can use antiviral vaccines to prevent dementia.

Overall, we need more research exploring in greater detail how infections are linked with dementia. This will help us understand the root causes of dementia and design potential therapies.

Ibrahim Javed, Enterprise and NHMRC Emerging Leadership Fellow, UniSA Clinical & Health Sciences, University of South Australia

This article is republished from The Conversation under a Creative Commons license. Read the original article.