In vivo gene therapies correct mutations within the body

A new generation of treatments is using CRISPR, viral vectors, and nanoparticles to modify genes directly inside the body; Brazil is broadening its research efforts in the field

Daniel Dieb

Black and white digital image, with highlights in tones of blue, of a DNA double helix, with glowing particles and scattered light against a dark background, suggesting a microscopic environment.

In medical records from the Children’s Hospital of Philadelphia (CHOP), he was known only as Patient Eta. The newborn, whose family chose not to share his name, had unusually high blood ammonia levels.

The diagnosis was CPS1 deficiency, a rare genetic disorder of the urea cycle. The sole available treatment was a liver transplant, but the procedure would only be possible when the child was older and clinically stable—and even if successful, it would not guarantee normal neurological development.

Between the diagnosis and that window of opportunity lay a significant period of risk.

Rather than simply wait, the hospital’s team developed an in vivo gene therapy specifically for the genetic mutation in question: a base editor delivered directly to the liver using lipid nanoparticles. The entire process, from diagnosis to first dose, took about six months.

From personalized production to direct delivery

In vivo therapies have emerged as an alternative to ex vivo methods, in which the patient’s cells are removed, genetically modified in a lab under strict conditions, and then infused back into the patient; a, personalized, time-consuming, and expensive process that offers no economies of scale.

“A different product for every patient,” says Bryan Strauss, a researcher at Brazil’s National Institute for Gene Therapy (Intergen).

With in vivo therapies, by contrast, the therapeutic component (a viral vector or a lipid nanoparticle) is delivered directly into the body and genetic modification occurs within the patient themselves.

Delivering the therapeutic component is the central challenge of these therapies. The most established approach is to use adeno-associated viruses (AAVs), which are modified to carry genetic material to specific cells.

More recently, lipid nanoparticles (LNPs)—the same platform used in mRNA COVID-19 vaccines—have become a popular synthetic option because they are easier to manufacture and allow for repeat dosing.

Ricardo Weinlich, a senior researcher at Einstein Hospital Israelita, highlights two major challenges for in vivo therapy.

“The first is efficiently delivering to the target cell. The second is avoiding cells you do not want to affect, which we call targeting,” explains Weinlich.

Editing unintended locations of the genome can have unpredictable consequences. Identifying these off-target effects in advance is now a key requirement for approval from regulatory bodies.

Adding genes and correcting mutations

The in vivo approach is not new. Luxturna and Zolgensma, the first gene therapies approved in Brazil, are administered directly into the body, although they use gene addition rather than gene editing.

What has changed is the modification technology: the new generation of therapies not only delivers a functional gene, it can directly correct the genetic error that causes the disease.

Tools like CRISPR have proven that it is possible to edit genes inside the human body with sufficient precision and safety to move onto clinical applications.

“With CRISPR, we are not adding a gene,” Strauss says. “We are literally correcting the defect.”

Remaining economic questions

There are also economic differences between in vivo and ex vivo methods. Ex vivo therapy requires infrastructure for personalized manufacturing processes: clean rooms, specialized staff, and a cold chain for custom-made products.

With in vivo therapies, the same batch can be used for many patients, creating potential for cost reductions. Despite this, the price remains prohibitive. Viral vector–based therapies can cost between US$1 million and US$4 million per dose.

Milena Soares, a researcher at the Oswaldo Cruz Foundation (FIOCRUZ) in Bahia, says that ensuring good practices is expensive, largely due to the cost of personnel training and retention, as well as the high prices of inputs, many of which are imported and subject to taxes.

Einstein’s Weinlich points out that the equation changes when in vivo gene therapy is compared to existing treatments.

“What we often fail to consider is how much it costs over time to treat these patients using conventional therapies. These new treatment approaches are curing the patient, or at least profoundly changing the course of the disease,” says Weinlich.

Another obstacle is regulatory approval. According to Soares, Brazil’s Health Regulatory Agency (ANVISA) is facing the challenge with limited personnel, who still require specialized training because gene therapy is a relatively new field.

Even so, she believes a gene therapy developed in Brazil could receive provisional approval within the next two to three years. “There is no point making an investment if there is no continuity,” warns the FIOCRUZ researcher.

For that to happen, she argues, the Brazilian private sector needs to get involved. “As much as we in academia are working on this, we are not manufacturers. We need private Brazilian companies to play a role—they are essential to the development of the country’s medical-industrial complex.”

Brazil joins the race for gene therapies

Brazil is steadily making progress in the field. A study by the Federal University of Rio Grande do Sul (UFRGS) ranked the country 12th worldwide in the number of clinical studies of gene therapy, and first among Latin American countries.

At FIOCRUZ Bahia, Milena Soares and her colleagues are developing a gene therapy for the cardiac sequelae of Chagas disease, a condition that affects millions of Brazilians.

“We are not treating the infection itself, but the heart disease caused by Trypanosoma cruzi,” says Soares.

The same group is also investigating ways to eliminate viral reservoirs of HIV and human T-cell lymphotropic virus (HTLV), two incurable conditions that currently require lifelong treatment.

In January this year, the first ever infusion of GB221, a gene therapy for type 1 spinal muscular atrophy (SMA), was administered at Hospital de Clínicas de Porto Alegre (HCPA) as part of the world’s first human clinical trial of the treatment. The trial is being led by FIOCRUZ, with support from Brazil’s Ministry of Health, in partnership with the US biotechnology company Gemma Biotherapeutics, which owns the technology.

Scientific advances alone, however, will not solve the challenge of access to these therapies. There is another obstacle beyond regulation and manufacturing issues: when mRNA COVID-19 vaccines were introduced, some people feared that the genetic material would alter human DNA—which does not happen.

“Some people claimed that the vaccines were causing genetic alterations,” Weinlich recalls.

Gene therapies, however, are designed to do exactly what mRNA vaccines have been accused of doing, and society needs to be prepared for that.

Science needs to get the public on board, the Einstein researcher argues, to ensure people understand the health benefits that in vivo gene therapies can provide. “Otherwise the technology will be dead on arrival,” he says.

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