Amazing Science

Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype and poor outcomes. Using single-cell RNA-Seq, we identified glioblastoma cellular populations with elevated HML-2 transcripts in neural progenitor–like cells (NPC-like) that drive cellular plasticity. Using CRISPR interference, we demonstrate that HML-2 critically maintained glioblastoma stemness and tumorigenesis in both glioblastoma neurospheres and intracranial orthotopic murine models.

Additionally, we demonstrate that HML-2 critically regulated embryonic stem cell programs in NPC-derived astroglia and altered their 3D cellular morphology by activating the nuclear transcription factor OCT4, which binds to an HML-2–specific long-terminal repeat (LTR5Hs). Moreover, we discovered that some glioblastoma cells formed immature retroviral virions, and inhibiting HML-2 expression with antiretroviral drugs reduced reverse transcriptase activity in the extracellular compartment, tumor viability, and pluripotency. Our results suggest that HML-2 fundamentally contributes to the glioblastoma stem cell niche. Because persistence of glioblastoma stem cells is considered responsible for treatment resistance and recurrence, HML-2 may serve as a unique therapeutic target.

Published in JCI (July 3, 2023):

https://doi.org/10.1172/JCI167929 

Researchers recently discovered an unexpected link between the progression of ALS and PEG10, a protein traditionally known for its role in placental development. Overabundance of this protein in nerve tissue has been observed to alter cell behavior contributing to ALS. The team is now studying the molecular pathways involved with a view to inhibiting this rogue protein, potentially paving the way for new therapeutics.

Key facts:

1. The ancient, virus-like protein PEG10, typically associated with placental development, has been linked to the progression of ALS when present in high levels in nerve tissue.
2. The research marks the first time PEG10 has been connected to ALS, with its accumulation seen as a hallmark of the disease.
3. Research findings suggest that inhibiting the rogue PEG10 protein could potentially lead to a new class of therapeutics for ALS.

More than 5,000 people are diagnosed annually with ALS (amyotrophic lateral sclerosis), a fatal, neurodegenerative disease that attacks nerve cells in the brain and spinal cord, gradually robbing people of the ability to speak, move, eat and breathe. To date, only a handful of drugs exist to moderately slow its progression. There is no cure. But CU Boulder researchers have identified a surprising new player in the disease—an ancient, virus-like protein that is best known, paradoxically, for its essential role in enabling placental development. The findings were recently published in the journal eLife. “Our work suggests that when this strange protein known as PEG10 is present at high levels in nerve tissue, it changes cell behavior in ways that contribute to ALS,” said senior author Alexandra Whiteley, assistant professor in the Department of Biochemistry. Whiteley’s lab is now working to understand the molecular pathways involved and to find a way of inhibiting the rogue protein. “It is early days still, but the hope is this could potentially lead to an entirely new class of potential therapeutics to get at the root cause of this disease.”

Ancient viruses with modern-day impact

Mounting research suggests about half the human genome is made up of bits of DNA left behind by viruses (known as retroviruses) and similar virus-like parasites, known as transposons, which infected our primate ancestors 30-50 million years ago. Some, like HIV, are well known for their ability to infect new cells and cause disease. Others, like wolves who have lost their fangs, have become domesticated over time, losing their ability to replicate while continuing to pass from generation to generation, shaping human evolution and health. PEG10, or Paternally Expressed Gene 10, is one such “domesticated retrotransposon.” Studies show it likely played a key role in enabling mammals to develop placentas—a critical step in human evolution. But like a viral Jekyll and Hyde, when it’s overly abundant in the wrong places, it may also fuel disease, including certain cancers and another rare neurological disorder called Angelman’s syndrome, studies suggest. Whiteley’s research is the first to link the virus-like protein to ALS, showing that PEG10 is present in high levels in the spinal cord tissue of ALS patients where it likely interferes with the machinery enabling brain and nerve cells to communicate. “It appears that PEG10 accumulation is a hallmark of ALS,” said Whiteley, who has already secured a patent for PEG10 as a biomarker, or way of diagnosing, the disease.

Too much protein in the wrong places

Whiteley did not set out to study ALS, or ancient viruses. Instead, she studies how cells get rid of extra protein, as too much of the typically good thing has been implicated in other neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Her lab is one of a half-dozen in the world to study a class of genes called ubiquilins, which serve to keep problem proteins from accumulating in cells. In 2011, a study linked a mutation in the ubiquilin-2 gene (UBQLN2) to some cases of familial ALS, which makes up about 10% of ALS cases. The other 90% are sporadic, meaning they are not believed to be inherited. But it has remained unclear how the faulty gene might fuel the deadly disease. Using laboratory techniques and animal models, Whiteley and colleagues at Harvard Medical School first set out to determine which proteins pile up when the UBQLN2 misfires and fails to put the brakes on. Among thousands of possible proteins, PEG10 topped the list. Then Whiteley and her colleagues collected the spinal tissue of deceased ALS patients (provided by the medical research foundation Target ALS) and used protein analysis, or proteomics, to see which if any seemed overexpressed.

Again, among more than 7,000 possible proteins, PEG10 was in the top five. In a separate experiment, the team found that with the ubiquilin brakes essentially broken, the PEG10 protein piles up and disrupts the development of axons—the cords which carry electrical signals from the brain to the body. PEG10 was over-expressed in the tissue of individuals with both sporadic and familial ALS, the study found, meaning the virus-like protein may be playing a key role in both. “The fact that PEG10 is likely contributing to this disease means we may have a new target for treating ALS,” she said. “For a terrible disease in which there are no effective therapeutics that lengthen lifespan more than a couple of months, that could be huge.” The research could also lead to a better understanding of other diseases that result from protein accumulation, as well as keener insight into how ancient viruses influence health. In this case, Whiteley said, the so-called “domesticated” virus could a be rearing its fangs again. “Domesticated is a relative term, as these virus-like activities may be a driver of neurodegenerative disease,” she said. “And in this case, what is good for the placenta may be bad for neural tissue.”

Original research published in eLIfe(May 23, 2023):

 https://doi.org/10.7554/eLife.79452

A clinical trial of an experimental universal influenza vaccine developed by researchers at the National Institute of Allergy and Infectious Diseases’ (NIAID) Vaccine Research Center (VRC), part of the National Institutes of Health, has begun enrolling volunteers at Duke University in Durham, North Carolina. This Phase 1 trial will test the experimental vaccine, known as H1ssF-3928 mRNA-LNP, for safety and its ability to induce an immune response.

The trial will enroll up to 50 healthy volunteers aged 18 through 49. Three groups of study participants (10 participants each) will be vaccinated with 10, 25 and 50 micrograms of the experimental vaccine, respectively. After evaluation of the data to determine an optimum dosage, an additional 10 participants will be enrolled to receive the optimum dosage. The study also will include a group of participants who will receive a current quadrivalent seasonal influenza vaccine. This will allow the researchers a point of direct comparison between the immunogenicity and safety of the candidate vaccine and available seasonal flu vaccines. Participants will be regularly evaluated to assess the vaccine’s safety (and, secondarily, its efficacy) and will receive follow-up appointments for up to one year after vaccination.

Seasonal influenza, or flu, kills thousands of people in the United States each year. The Centers for Disease Control and Prevention estimates that between 2010 and 2020, between 12,000 and 52,000 people died of flu in the United States annually. Although annual seasonal flu vaccines are valuable tools in controlling the spread and severity of influenza, they do not provide immunity against every flu strain. Each year, before the flu season begins, scientific experts must predict which influenza strains are likely to be most common during the upcoming months and then select three or four of these strains to include in the next seasonal flu vaccine. Vaccine manufacturers then need time to produce and distribute the vaccine—during which the dominant strains of the virus can change in unexpected ways, potentially decreasing the efficacy of the vaccine. An effective universal flu vaccine could eliminate these problems by protecting its recipients against a wide variety of strains and ideally providing durable long-term immunity, so people would not need to be vaccinated every year. “A universal influenza vaccine would be a major public health achievement and could eliminate the need for both annual development of seasonal influenza vaccines, as well as the need for patients to get a flu shot each year,” said Acting NIAID Director Hugh Auchincloss, M.D. “Moreover, some strains of influenza virus have significant pandemic potential. A universal flu vaccine could serve as an important line of defense against the spread of a future flu pandemic.”

Aging, or senescent cells, which stop dividing but don’t die, can accumulate in the body over the years and fuel chronic inflammation that contributes to conditions such as cancer and degenerative disorders. In mice, eliminating senescent cells from aging tissues can restore tissue balance and lead to an increased healthy lifespan. Now a team led by investigators at Massachusetts General Hospital (MGH) has found that the immune response to a virus that is ubiquitously present in human tissues can detect and eliminate senescent cells in the skin.

For the study, which is published in Cell, the scientists analyzed young and old human skin samples to learn more about the clearance of senescent cells in human tissue. The researchers found more senescent cells in the old skin compared with young skin samples. However, in the samples from old individuals, the number of senescent cells did not increase as individuals got progressively older, suggesting that some type of mechanism kicks in to keep them in check. Experiments suggested that once a person becomes elderly, certain immune cells called killer CD4+ T cells are responsible for keeping senescent cells from increasing. Indeed, higher numbers of killer CD4+ T cells in tissue samples were associated with reduced numbers of senescent cells in old skin. When they assessed how killer CD4+ T cells keep senescent cells in check, the researchers found that aging skin cells express a protein, or antigen, produced by human cytomegalovirus, a pervasive herpesvirus that establishes lifelong latent infection in most humans without any symptoms. By expressing this protein, senescent cells become targets for attack by killer CD4+ T cells.

“Our study has revealed that immune responses to human cytomegalovirus contribute to maintaining the balance of aging organs,” says senior author Shawn Demehri, MD, PhD, director of the High Risk Skin Cancer Clinic at MGH and an associate professor of Dermatology at Harvard Medical School. “Most of us are infected with human cytomegalovirus, and our immune system has evolved to eliminate cells, including senescent cells, that upregulate the expression of cytomegalovirus antigens.” These findings, which highlight a beneficial function of viruses living in our body, could have a variety of clinical applications. “Our research enables a new therapeutic approach to eliminate aging cells by boosting the anti-viral immune response,” says Demehri. “We are interested in utilizing the immune response to cytomegalovirus as a therapy to eliminate senescent cells in diseases like cancer, fibrosis and degenerative diseases.” Demehri notes that the work may also lead to advances in cosmetic dermatology, for example in the development of new treatments to make skin look younger.

Mitochondria are critical organelles that form networks within our cells, generate energy dynamically, contribute to diverse cell and organ function, and produce a variety of critical signaling molecules, such as cortisol. This intracellular microbiome can differ between cells, tissues, and organs. Mitochondria can change with disease, age, and in response to the environment. Single nucleotide variants in the circular genomes of human mitochondrial DNA are associated with many different life-threatening diseases. Mitochondrial DNA base editing tools have established novel disease models and represent a new possibility toward personalized gene therapies for the treatment of mtDNA-based disorders.

Researchers discovered a potential link between "endogenous retroviruses" present in the human genome and the development of neurodegenerative diseases.

Summary: Researchers discovered a potential link between “endogenous retroviruses” present in the human genome and the development of neurodegenerative diseases. Their study found that these ancient viral remnants might influence the spread of protein aggregates commonly associated with certain dementias. While these retroviruses don’t trigger neurodegeneration, they may exacerbate the disease process. This discovery offers new potential therapeutic avenues, such as suppressing gene expression or neutralizing viral proteins.

Key Facts:

1. “Endogenous retroviruses”, ancient viral remnants in human DNA, might contribute to neurodegenerative disease progression.
2. HERV-W and HERV-K, two such retroviruses, were found to aid in the transport of tau aggregates, protein clumps associated with diseases like Alzheimer’s.
3. Potential therapeutic approaches include suppressing the retroviruses or neutralizing their proteins, possibly with antibodies.

Source: DZNE

Genetic remnants of viruses that are naturally present in the human genome could affect the development of neurodegenerative diseases. Researchers at DZNE come to this conclusion on the basis of studies on cell cultures. They report on this in the journal Nature Communications. In their view, such “endogenous retroviruses” could contribute to the spread of aberrant protein aggregates – hallmarks of certain dementias – in the brain. Thus, these viral relicts would be potential targets for therapies. It has been suspected for some time that viral infections contribute to the genesis and development of neurodegenerative diseases. Laboratory studies by DZNE scientists now suggest a mechanism that, although related to viruses, does not require infection by external pathogens. According to this study, the culprits would be “endogenous retroviruses” that are naturally present in the human genome. “During evolution, genes from numerous viruses have accumulated in our DNA. Most of these gene sequences are mutated and normally muted,” explained Ina Vorberg, research group leader at DZNE and a professor at the University of Bonn. “However, there is evidence that endogenous retroviruses are activated under certain conditions and contribute to cancer and neurodegenerative diseases. Indeed, proteins or other gene products derived from such retroviruses are found in the blood or tissue of patients.”

Experiments with Tau Aggregates 

Vorberg followed this trail together with colleagues from Bonn and Munich. Using cell cultures, the researchers simulated the situation in which human cells produce certain proteins from the envelope of endogenous retroviruses. Specifically, this involved HERV-W and HERV K – both viruses are present in the human genome but are usually dormant. However, studies indicate that HERV-W is activated in multiple sclerosis and HERV-K in the neurological disease “amyotrophic lateral sclerosis” (ALS) and in frontotemporal dementia (FTD). Now, Vorberg’s team found that the viral proteins facilitate the transport of so-called tau aggregates from cell to cell. “Tau aggregates” are tiny protein clumps that occur in the brains of people affected by certain neurodegenerative diseases – these include Alzheimer’s disease and FTD. “Certainly, conditions in the brain are much more complex than our cellular model system can replicate them. Nevertheless, our experiments show that endogenous retroviruses can influence the spread of tau aggregates between cells,” Vorberg said. “Endogenous retroviruses would thus not be triggers of neurodegeneration, but could fuel the disease process once it is already underway.”

Viral Transport Mediators

The current research and earlier studies by Vorberg’s team suggest that viral proteins serve as transport mediators for tau aggregates because they insert into the cell membrane and into the membrane of so-called extracellular vesicles: These are small fat bubbles that are naturally secreted by cells. “For the transport of tau aggregates from cell to cell, we see two pathways in particular. Transfer between cells that are in direct contact, and transport within vesicles that act as cargo capsules, so to speak, and pass from one cell to another to eventually merge with it,” Vorberg explained. “In both scenarios, membranes have to fuse. Proteins from the envelope of viruses can promote this process. That’s because many viruses are adapted to fuse with host cells. “This happens by means of special proteins that viruses carry on their surfaces. If precisely these proteins are incorporated into the cell membrane and the membrane of extracellular vesicles, it is understandable that the tau aggregates then spread more easily.”

Starting Points for Therapy

In the course of the natural aging process, the regulation of genes can change – originally “dormant” endogenous retroviruses could be “awakened” as a result. Indeed, the symptoms of most neurodegenerative diseases do not manifest until older age. This raises two conceivable approaches to therapy. “On the one hand, one could try to specifically suppress gene expression, that is, to inactivate the endogenous retroviruses again. That would get to the root of the problem,” Vorberg said. “But you could also start elsewhere and try to neutralize the viral proteins – for example, with antibodies.”

Searching for Antibodies

In the opinion of the researchers, it is likely that dementia patients with tau aggregates carry increased amounts of such antibodies. If it were possible to isolate these and reproduce them using biotechnological methods, it might be possible to develop a passive vaccine. Thus, in collaboration with DZNE colleagues in Berlin and Bonn, Vorberg’s team aims to specifically search for such antibodies in patients. In addition, the scientists are considering antiviral drugs. In cell culture, they have already found that such agents can actually stop the spread of protein aggregates. “This is another approach we intend to pursue,” said Vorberg.

Research cited published in Nature (Aug. 18, 2023):

https://doi.org/10.1038/s41467-023-40632-z 

The development of cancer neoantigen vaccines that prime the anti-tumor immune responses has been hindered in part by challenges in delivery of neoantigens to the tumor. Here, using the model antigen ovalbumin (OVA) in a melanoma model, we demonstrate a chimeric antigenic peptide influenza virus (CAP-Flu) system for delivery of antigenic peptides bound to influenza A virus (IAV) to the lung. We conjugated attenuated IAVs with the innate immunostimulatory agent CpG and, after intranasal administration to the mouse lung, observed increased immune cell infiltration to the tumor.

OVA was then covalently displayed on IAV-CPG using click chemistry. Vaccination with this construct yielded robust antigen uptake by dendritic cells, a specific immune cell response and a significant increase in tumor-infiltrating lymphocytes compared to peptides alone. Lastly, we engineered the IAV to express anti-PD1-L1 nanobodies that further enhanced regression of lung metastases and prolonged mouse survival after rechallenge. Engineered IAVs can be equipped with any tumor neoantigen of interest to generate lung cancer vaccines. A cancer vaccine is delivered to the lung by an engineered attenuated influenza virus.

Published in Nature Biotechnology:

https://doi.org/10.1038/s41587-023-01796-7 

Gene therapies have made spectacular progress in delivering new cures for previously intractable disease, but they remain the world’s most expensive treatments by far. Now companies are replacing the virus in gene therapies with new delivery technologies that promise not only to overcome the limitations of viral vectors but to slash production costs too. Moderna and Generation Bio teamed up recently to develop non-viral gene therapies for liver and immune-related conditions, in a deal that builds on Generation Bio’s lipid nanoparticle (LNP) delivery platform. The collaboration is part of a growing trend to swap virus-driven gene therapeutics for innovative nucleic acid delivery platforms that escape the high costs and technical limitations of viral vectors.

Engineered lipid or protein nanobodies, DNA-based nanocarriers, and novel physicochemical methods point the way toward re-dosable genetic medicines (Table 1). Virus-based vectors — particularly those based on adeno-associated virus (AAV) and lentiviruses — have dominated the first wave of gene therapies to gain regulatory approval. But their widespread deployment in dozens of clinical trials has exposed their limitations very clearly. “One of the issues is just the biomass needed to produce a sufficient amount, like AAV at the scale and in the doses needed for large indications,” says Akin Akinc, CEO of Aera Therapeutics, a company developing a protein-nanoparticle-based delivery system. AAV vectors are further limited by their 4.7-kilobase packaging capacity; poor tissue selectivity; risk of liver toxicity; and immunogenicity, which eliminates the possibility of redosing. Lentiviral vectors and, to a lesser extent, AAV vectors also elicit oncogenicity concerns arising from chromosomal integration and insertional mutagenesis. Moreover, the theoretical risk of replication-competent viruses emerging from recombination events during lentiviral production necessitates extensive testing in patients.

Researchers reviewed data on the incidence of autoimmune diseases in the post-acute coronavirus disease 2019 period.

Background

COVID-19 has caused unprecedented morbidity and mortality across the globe. The immune protection conferred by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and prior COVID-19 history, coupled with developing effective therapeutic agents, has reduced COVID-19-associated mortality. However, post-COVID-19 conditions continue to increase, particularly new-onset autoimmune diseases in COVID-19 convalescents. Autoimmune diseases have been reported following COVID-19 among adults; however, the prevalence and magnitude of the diseases, and the incidence risks among individuals infected with SARS-CoV-2, compared to uninfected individuals, are not well-characterized. Improving understanding of the impact of COVID-19 on the risk of developing post-acute COVID-19 complications, such as autoimmune disease, could aid in implementing preventive measures and initiating prompt treatment to prevent COVID-19-associated morbidities. The findings would also be highly relevant for future pandemics and to analyze the long-term protective effects of COVID-19 vaccines.

About the review

In the review, researchers presented findings of two large-scale cohort studies, evaluating the incidence of autoimmune diseases following acute SARS-CoV-2 infections using participants' electronic medical records.

Evidence on post-COVID autoimmune disease obtained before the studies

Studies comprising pediatric COVID-19 patients suffering from multisystem inflammatory syndrome among children (MIS-C) have indicated that COVID-19 results in dysregulated immunological responses. The clinical manifestations of MIS-C overlap with hyperinflammatory syndromes, including macrophage activation syndrome, Kawasaki disease, and toxic shock syndrome. The pathophysiology of COVID-19-associated immunological dysfunction includes molecular mimicry by SARS-CoV-2 proteins, multiorgan involvement due to the presence of angiotensin-converting enzyme 2 (ACE2) receptors, essential for SARS-CoV-2 entry into host cells, bystander immune cell activation, autoantigen release following SARS-CoV-2-induced tissue damage, superantigen-regulated lymphocyte activation, and epitope spread. Additionally, factors such as genetic susceptibility, age, and comorbidities may contribute to COVID-19 pathogenesis. A previous study comparing the immune responses in SARS-CoV-2 infection and autoimmune disease reported that tissue damage in both conditions is mainly immune-regulated, demonstrated by the presence of anti-nuclear antibodies, anti-Ro/SSA antibodies, and lupus anticoagulant cold agglutinins in both conditions. A retrospective analysis was performed from January 31, 2020, to June 30, 2021, using the Clinical Practice Research Datalink Aurum database, comprising data from 458,147 and 1,818,929 SARS-CoV-2-infected and uninfected adults, respectively, residing in England. A study preprint reported that the incidence of inflammatory bowel disease, psoriasis, and type 1 diabetes was significantly related to COVID-19.

Findings of the two cohort studies assessed post-COVID autoimmune disease

Chang et al. utilized the TriNetX health research network, comprising six million adults across 48 health organizations globally. The propensity score-matched SARS-CoV-2-infected and uninfected groups comprised 887,455 COVID-19 vaccinees each. Post-COVID-19 autoimmune disease incidence was evaluated between January 1, 2020, and December 31, 2021. At six months of follow-up, autoimmune disease incidence was significantly greater in SARS-CoV-2-infected individuals, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, type 1 diabetes, and inflammatory bowel disease, with adjusted hazards ratios (aHR) of 2.99,2.98, 1.96, 2.68, and 1.78, respectively. Post-COVID autoimmune disease risk was consistent across ages. Tesch et al. conducted a study, yet to be peer-reviewed, to evaluate autoimmune disease risks among 640,701 unvaccinated individuals having polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infections in 2020. The findings showed that COVID-19 patients were 43.0% more likely to acquire autoimmune conditions, within three to 15.0 months of infection, compared to over one million age- and sex-matched uninfected individuals. Among autoimmune diseases, the incidence rate ratio (IRR) values were the highest for vasculitis. Further, among those with prior history of autoimmune diseases, COVID-19 resulted in a 23.0% higher risk of another autoimmune disease. Generally, most autoimmune diseases were not COVID-19-specific; however, an essential aspect of SARS-CoV-2 infection was a considerable rise in the incidence and spectrum of autoimmune diseases following acute COVID-19.

Conclusions

Based on the review findings, COVID-19 elevates autoimmune disease risks. Due to the retrospective study designs, the two cohort studies could not provide a causal association between COVID-19 and autoimmune disease development. However, the temporal relationship with COVID-19 history provides reliable and compelling evidence that COVID-19 is associated with elevated autoimmune disease development risks. Health governments and authorities must conduct future studies on the topic to obtain national data and increase the generalizability of the findings. The definitive mechanisms, including genetic and epigenetic predilection, underlying the association and related pathophysiology are not completely understood. However, further research must be performed using particular gene-deficient experimental animals, bioinformatic analysis, and biological approaches, e.g., analyzing transcriptomic pandemic data to obtain genomic signatures, and host responses to viral triggers must be evaluated.

Research cited published (April 12, 2023) In Nature Reviews Rheumatology:

https://www.nature.com/articles/s41584-023-00964-y 

A research team led by gene editing pioneer David R. Liu, PhD, reports the application of base editing technology to develop a one-time treatment for spinal muscular atrophy (SMA), showing promising effectiveness in cell and mouse models. Liu, a professor at Harvard University, the Broad Institute, and an investigator with the Howard Hughes Medical Institute, together with 16 co-authors, published their findings today in Science, in a report entitled, “Base editing rescue of spinal muscular atrophy in cells and in mice.”

The paper is the first one published in a peer-reviewed journal that details a base editing approach to treating SMA—the leading genetic cause of infant mortality. Two months ago, Benjamin P. Kleinstiver, PhD, assistant professor in the Center for Genomic Medicine at Massachusetts General Hospital (MGH) and Harvard Medical School, and 12 co-authors posted a related preprint on bioRxiv detailing successful results from their study to optimize and implement a base editing treatment for SMA. In SMA, patients have either a loss of, or mutations in, the SMN1 gene. The result is a lack of its corresponding protein SMN, which is critical to cellular functions that include those required for embryo development. Liu and co-authors detailed how they restored SMN protein abundance to normal levels and rescued disease phenotypes in cell and mouse models of SMA by developing one-time genome editing approaches targeting another gene, called SMN2.

SMN2 differs from SMN1 at just one position—a single C-to-T mutation in exon 7. The result is a defective truncated SMN protein that fails to fully compensate for the loss of SMN1, but which provides just enough SMN protein activity to allow babies to be born with SMA. In the most common SMA cases (type 1), those babies typically live less than two years without treatment. Liu and colleagues developed a customized base editor (out of more than 40 tested) that directly converts SMN2 to the same sequence as SMN1 by reversing the C-to-T mutation that occurred during the duplication of SMN1 to SMN2.

The investigators reported that their strategy converted SMN2 to SMN1 with near-ideal editing efficiency of 99% in cells, fully restoring SMN protein levels ~40-fold to normal levels, while generating minimal off-target edits. “Because all SMA patients have SMN2—otherwise loss of SMN1 would not allow them to be born—this base editing approach to treating SMA also should be applicable to all SMA patients, regardless of the specific mutation that caused their SMN1 loss,” Liu said.