CRISPR potrebbe essere la prossima superarma contro i virus?

Il potenziale di CRISPR oltre l’editing genetico

Since its discovery, CRISPR (“Clustered Regularly Interspaced Short Palindromic Repeats”), which won the 2020 Nobel Prize in Chemistry, has revolutionized medicine and biotechnology.

Fonte: Nobel Prize

Questo perché CRISPR è il primo metodo di editing genetico che consente un targeting molto preciso di una sequenza genetica specifica, permettendo di correggere errori genetici sia in vitro che in vivo senza rischiare mutazioni indesiderate.

Ciò è importante poiché l’inserimento genico non diretto è stato collegato a problemi gravi, in particolare rischi di cancro, rendendo il loro uso terapeutico difficile e controverso.

CRISPR può essere usato in diversi modi per interrompere un gene già presente, cancellare una sequenza specifica o modificare/inserire la sequenza genetica corretta.

Fonte: CRISPR Therapeutics

Questo si è trasformato in una svolta medica con l’approvazione FDA per la prima terapia basata su CRISPR nel 2023, sviluppata da CRISPR Therapeutics (CRSP )  per malattie del sangue genetiche (segui il link per un report dedicato su CRISPR Therapeutics).

Tuttavia, l’editing genico preciso controllato dall’uomo non è ciò per cui CRISPR è stato usato in natura. Questo è, prima di tutto, uno strumento antivirale che i batteri usano per sopravvivere agli attacchi dei virus.

Quindi sorge la domanda se CRISPR potrebbe essere usato allo stesso modo per trattare i virus umani. Specialmente quelli più difficili da combattere con vaccini o trattamenti antivirali.

Questa è l’idea investigata da ricercatori dell’Islamic Azad University (SRBIAU) (Iran), Semnan University of Medical Sciences (Iran), Shahid Beheshti University of Medical Sciences (Iran), Shahroud University of Medical Sciences (Iran) e University of Bergen (Norvegia).

Hanno pubblicato i loro risultati in una revisione sistematica della ricerca in corso nel campo su MDPI, sotto il titolo “Progress in CRISPR Technology for Antiviral Treatments: Genome Editing as a Potential Cure for Chronic Viral Infections”.

Le origini naturali di CRISPR come difesa virale

La maggior parte dei batteri è costantemente minacciata da virus specializzati nell’attaccarli, chiamati batteriofagi (letteralmente “mangia-batteri”). I fagi agiscono atterrando sul batterio e iniettandogli il loro materiale genetico, per replicare più virus.

Fonte: Innovative Genomics

Ogni sequenza genetica CRISPR trovata all’interno di un singolo CRISPR batterico deriva da un frammento di DNA di un batteriofago che aveva precedentemente infettato il procariota o uno dei suoi antenati.

In questo modo, il sistema CRISPR può riconoscere il materiale genetico del batteriofago e tagliarlo a pezzi prima che riesca a riprodursi in nuove particelle virali.

Questo forma una sorta di “immunità acquisita” per i batteri contro i virus fagi. CRISPR è presente in circa il 50 % dei genomi batterici sequenziati.

Considerando quanto siano diffusi i sistemi CRISPR e quanto siano importanti contro le infezioni virali per i batteri, questo metodo potrebbe essere usato anche per trattare i virus negli esseri umani?

Targeting Chronic Infections With CRISPR

Perché le infezioni croniche?

When discussing viral infection, chronic infections are the prime concern for doctors. This includes viruses like HIV or hepatitis.

Un problema specifico di queste malattie che permette loro di eludere sia il trattamento sia il sistema immunitario è che possono andare in dormienza, con il materiale genetico virale incorporato nella cellula, a volte silente per anni.

Sometimes, the provirus switches to an inactive mode that cannot be transcribed, which raises an issue.

Not only can the human immune system not attack these latent reservoirs, but the antiretroviral medications also fail to act upon these non-transcribing sections. Some of these HIV-1 reservoirs can survive for up to 60 years in CD4+ T cells.

There are a few ways CRISPR technology could be used to target these chronic viral infections.

CRISPR può aiutare a curare HIV/AIDS?

One option is through genetic engineering, to create human cells that are missing the receptors required for the viral infection to work. In the case of AIDS/HIV, modified immune CD4+ T cell without the CCR5 & CXCR4 co-receptors become resistant to the virus and can block its entry.

This approach seems to work in the lab but will require extensive animal studies and then human trials to determine if it is efficient and safe enough to become a reliable cure for the disease.

The same method of modifying the human cells is considered for hepatitis C. CRISPR-Cas13a targeting the entry site of the virus into liver cells prevents the virus replication effectively with extremely limited damages to the liver cells, much lower than the ones caused by the virus.

CRISPR vs. infezioni dormienti dell’epatite B

Similar to HIV, the hepatitis B virus forms a latent viral reservoir using “covalently closed circular DNA” (cccDNA) in liver cells.

Studies in cultured cells indicated that CRISPR systems targeted against conserved sequences in the hepatitis B genome can successfully reduce 98% of hepatitis B’s DNA material.

Combattere l’HPV con CRISPR

Human papillomavirus, or HPV, is a sexually transmitted virus that can cause precancerous lesions that later on can turn into cancer, not only in the cervix but also in other organs. It, too, can become dormant.

Some vaccines for HPV exist, but do not cover all the types of HPVs, and cannot help with preexisting infections.

CRISPR systems can upregulate pRb, a host tumor-suppressor protein, blocking the growth of positive HPV cells and inhibiting their cancerous activity.

Usare CRISPR per affrontare il virus di Epstein–Barr (EBV)

Epstein–Barr virus, or EBV, is a virus that infects immune cells (lymphocytes B) and causes infectious mononucleosis, while sometimes it can develop into malignant cancers, like Burkitt’s lymphoma.

Here, too, modifying the immune cells can block their evolution toward cancer, effectively suppressing the worst effects of EBV.

CRISPR vs. approcci antivirali tradizionali

As we saw with the recent COVID pandemic, a recurring issue for vaccines is how to target a part of the virus that is stable and constant enough between strains for the vaccine to stay effective despite quick mutations.

This is because viruses are very good at modifying their surface proteins, the only ones accessible to antibodies created by the vaccines.

In contrast, CRISPR-Cas13d-based methods can target conserved genetic sequences coding for the capsid protein and RNA polymerase, which are necessary for the virus proliferation.

By focusing on these conserved areas, PAC-MAN aims to deliver broad-spectrum efficacy against various virus strains and even across related viruses.

The same method could be used for flu viruses, which are even more able to mutate constantly and evade existing vaccines.

For example, up to 92% of known influenza A strains were successfully targeted with just six crRNAs, and similar success was achieved with SARS-CoV-2 using 22 crRNAs.

CRISPR Antiviral Therapies: Prospettive future e limitazioni

Even if the CRISPR system is able to adapt to mutation, this is not entirely foolproof, as the continuous adaptation of bacteriophages to natural CRISPR systems proves. So while these methods might prove a big medical progress, it is unlikely to be a silver bullet either.

Off-target modification of the human genome is also a risk, especially with CRISPR-Cas9 systems, which can eventually cause mutation or toxicity of the treatment. This has been less of a concern for gene therapy of deadly genetic diseases without any cure, leading to the recent approval of these gene therapies.

For infectious diseases in larger populations, the FDA may take a harder line and more cautious approach, slowing down the path to commercialization of these therapies.

The delivery system of the CRISPR system into the host cells is also not trivial. Viral vectors or nanoparticles can create unwanted immune reactions or target other organs than the desired ones.

Progress in CRISPR therapy, from using other versions than Cas9 (like CRISPR-Cas12a), or new vectors more tolerated by the human body, will also benefit the progress of CRISPR antiviral therapies.

In addition, new methods like using Cas13, which target viral RNA without harming the host DNA, are especially suitable for a rapid response against RNA viruses like SARS-CoV-2.

Investire nell’innovazione CRISPR

Editas

Editas è stata fondata dalla co-scopritrice di CRISPR-Cas9 Jennifer Doudna. Editas ha iniziato a lavorare con Cas9 ma ora si concentra su una versione proprietaria di Cas12a che hanno ingegnerizzato: AsCas12a.

You can read more about Cas12a’s unique properties in our dedicated article “What Is CRISPR-Cas12a2? & Why Does It Matter?”.

Fonte: Editas

You can also read an overview of all of Jennifer Doudna’s companies in the corresponding article “Top Jennifer Doudna Companies to Watch.”

Editas is focused on Sickle Cell Disease (SCD) and beta-thalassemia, 2 diseases where it lost the race for first treatment approval to competitors CRISPR Therapeutics and BlueBirdBio.

Overall, the SCD program (recently renamed Reni-Cell) has been delayed several times, sparking concern among investors, and has since been refocused on in vivo therapy to distinguish it from already approved SCD therapies.

Nevertheless, Editas owns significant patents on CRISPR-Cas12, which has been used by researchers at the University of New South Wales, Australia, to develop a COVID-19 strip test, illustrating the technology’s potential beyond gene editing.

Editas also signed in 2023 a $50M deal with Vertex for the company to use Editas’ Cas9 IP.

Editas focuses on other CRISPR versions than the “classical” CRISPR-Cas9 and its research IP might come in handy in establishing partnerships and generating revenues without an FDA-approved product, on top of a cash runway going into 2026.

As Cas12a seems to become increasingly proven as a best-in-class method for multi-gene editing, Editas’ expertise and pipeline focus on this CRISPR variant might prove a winning bet in the long run.

(You can read more about CRISPR companies in our corresponding article “Top 5 CRISPR Companies To Invest In”.)

Ultime notizie e sviluppi sul titolo Editas (EDIT)

Studi citati:

^{1. Nouri, F., Alibabaei, F., Forouzanmehr, B., Tahmasebi, H., Oksenych, V., & Eslami, M. (2025). Progress in CRISPR Technology for Antiviral Treatments: Genome Editing as a Potential Cure for Chronic Viral Infections. Microbiology Research, 16(5), 104. https://doi.org/10.3390/microbiolres1605010}