Gene editing sees immune system make own therapeutic proteins inside body

CRISPR-based modification of haematopoietic stem cells has enabled durable, boostable antibody production in mouse models offering a programmable platform for treatment across infectious, genetic and metabolic diseases

A novel gene-editing strategy has enabled the immune system to function as a durable in vivo manufacturing platform for therapeutic proteins, with early evidence that even limited modification of stem cells can deliver sustained, boostable protection against infectious disease. The findings have demonstrated that targeted editing of haematopoietic stem cells can generate long-lived antibody responses in mice, with potential applications that extend from infectious disease to genetic disorders and cancer.

The study has shown that the approach can induce persistent production of highly potent antibodies that are typically difficult for the body to generate. By embedding genetic instructions directly into stem cells that give rise to B lymphocytes, the method bypasses the constraints of conventional vaccination and immune training. As a result, the immune system itself becomes a programmable source of therapeutic proteins.

“Our goal is to permanently impact the genome with a single injection, so that the body can make proteins of interest,” said Dr. Harald Hartweger, research assistant professor in the laboratory of molecular immunology led by Dr. Michel Nussenzweig at the Rockefeller University, New York, USA. 

“That protein could be an antibody that is universally protective against human immunodeficiency virus – HIV – or influenza but it could also be any therapeutic protein,” Hartweger added.

Conventional vaccines rely on exposure to antigens to prompt B cells to evolve protective antibodies. This model has proved effective when pathogens present stable and accessible targets. However, certain viruses, particularly HIV, evade immune recognition through structural complexity and glycan shielding that mimics host tissues. 

Broadly neutralising antibodies can overcome these defences but they arise only from rare precursor cells after prolonged and complex mutation processes. Even carefully designed vaccination strategies have failed to reliably induce such responses in most individuals.

Previous attempts to overcome these barriers have included sequential vaccination protocols designed to guide antibody evolution, as well as direct genetic modification of mature B cells to express broadly neutralising antibodies. Although technically successful, these strategies have suffered from limited durability, as edited mature B-cell populations decline over time.

To address this limitation the researchers shifted focus upstream to haematopoietic stem and progenitor cells which serve as the origin of all blood and immune cells. By introducing antibody-encoding genetic sequences into these stem cells, the team sought to establish a permanent blueprint that would propagate through subsequent generations of B cells. This design exploits a fundamental feature of the immune system, namely its capacity to expand rare but functionally advantageous cell populations.

“The immune system is inefficient, in that it produces a vast quantity of cells to protect itself. We wanted to take advantage of the immune system’s ability to amplify useful, rare cells,” Hartweger said.

Using clustered regularly interspaced short palindromic repeats (CRISPR) gene-editing technology, the researchers inserted sequences encoding protective antibodies into mouse model haematopoietic stem and progenitor cells. 

Following transplantation into recipient mice, these edited cells differentiated into B cells that carried the engineered genetic instructions. Subsequent administration of a conventional vaccine acted as a physiological trigger to activate and expand the modified cells.

The results have indicated that even a very small number of successfully edited stem cells can generate a robust immune response. Vaccination prompted expansion of the engineered B cells which matured into plasma cells and produced substantial quantities of antibodies. These responses persisted over extended periods and could be reactivated through booster immunisation. Importantly, the engineered cells retained normal immunological behaviour and conferred protection against disease. Mice programmed to express a broadly neutralising influenza antibody survived exposure to an otherwise lethal influenza infection.

Beyond antibody production, the platform has shown versatility in its ability to direct secretion of non-antibody proteins. This capability suggests potential utility in the treatment of genetic diseases characterised by absent or defective enzymes, as well as metabolic disorders that require sustained protein replacement. 

The researchers have also demonstrated that multiple antibody programmes can be introduced simultaneously into stem cells, enabling the immune system to produce a combination of therapeutic antibodies. Such multiplexing could reduce the likelihood of viral escape and support functional cures for rapidly mutating pathogens.

In parallel experiments, the team applied the same editing strategy to human haematopoietic stem cells, which subsequently differentiated into functional immune cells in experimental systems. This result provides an important indication that the platform could translate into clinical use, although substantial work remains to establish safety, efficacy and scalability.

“We have been working on difficult antibody problems for some time now – including HIV and hepatitis – and have generally sought to understand how the immune system makes antibodies,” said Nussenzweig. 

“The present study proposes a workaround for the antibody problem, a way to circumvent the possibility that we may never achieve a universal HIV vaccine while still providing a promising, long-lasting solution,” he added.

The approach represents a conceptual shift in immunotherapy. Rather than rely on the uncertain and often inefficient process of immune education, it programmes the cellular source of immunity to produce defined therapeutic outputs. This paradigm may offer a more reliable route to sustained protection or treatment, particularly in contexts where conventional vaccination or biologic therapy has proved inadequate.

Future work will aim to advance the platform towards clinical application. Planned studies include evaluation in non-human primate models to assess protection against HIV, as well as investigation into whether similar genetic programming can be applied to T lymphocytes. The broader objective is to establish a generalisable system for long-term, endogenous production of therapeutic proteins across a wide spectrum of diseases.

“We want to find a way to make any protein,” Hartweger said. 

“HIV antibodies, of course, but also solutions that address protein deficiencies and metabolic disease, as well as antibodies to treat inflammatory disease, influenza or cancer. This is a step in that direction, showing the feasibility of making life-saving proteins,” he concluded

For further reading please visit: 10.1126/science.adz8994