Nanopartikel Lipid Mempermudah Penyuntingan Gen Paru

Bagaimana Nanopartikel Lipid Memungkinkan Penyuntingan Gen Paru

Recently, some advanced gene editing therapies have been approved, notably for blood diseases like sickle cell disease. In theory, this opens the door to a lot more gene therapies, especially for rare and/or incurable diseases.

In practice, this is not so simple, as the gene editing technology first needs to reach the right organs and have a high enough transformation rate that enough of the organ’s cells are modified. It means that another way to improve gene therapies is not through better gene editing systems, like CRISPR, but through better delivery systems of the gene editing product.

This is what researchers at the Oregon State University and the University of Helsinki (Finland) have been working on. They published their latest results in Nature Communication¹, under the title “Synthesis of ionizable lipopolymers using split-Ugi reaction for pulmonary delivery of various size RNAs and gene editing”.

Tantangan dan Pendekatan dalam Pengantaran Gen

The idea of delivering genetic material to human cells for gene therapies is not a recent one, with tentative to do so ongoing since the 1980s. It has however been of limited success until recently, due to a conjunction of several reasons:

• Kesulitan untuk mengintegrasikan materi genetik ke dalam inti sel.
• Kesulitan menargetkan penyisipan gen, yang menyebabkan mutasi tidak diinginkan dan tingkat ekspresi gen yang tidak dapat diprediksi.
• Masalah dalam melewati membran sel oleh materi genetik.

The first two issues have been progressively getting better, even if still not entirely solved, thanks to technology like CRISPR that can direct genetic modification toward the cell nucleus and precisely edit a given part of the genome.

Delivery of the genetic material has been a harder problem to solve. Historically, modified viral particles or electric shock were used to modify the cell.

A more modern approach is using engineered lipid particles encapsulating the therapy, due to their ability to merge with the cell’s membrane. This is notably how most of the mRNA vaccines used during the Covid pandemic delivered their mRNA payload.

These particles must also contain chemical motifs that protect the mRNA molecules from systemic degradation and facilitate mRNA escape from the endosome to allow efficient mRNA translation into functional proteins within the cells.

So far, unique delivery methods have to be engineered for each new therapy, optimized for a specific size of mRNA or DNA material, and the targeted cells and organism. This has been a hindrance in the development of new therapies, and also a massive regulatory burden in the approval of new treatments.

Kimia Polimer Baru untuk Pengantaran Gen yang Lebih Aman

Polyethylene imine (PEI) is a chemical that has been used for gene delivery from lipid capsules in research before, thanks to its good performance in delivering genetic material. But it can also be toxic to cells, limiting its practical applications outside of cultured cells and for human medicine.

The researchers looked to solve that issue by using the so-called “Ugi multicomponent reaction” to modify the chemical structure of PEI by adding other chemicals to the polymer.

Sumber: Nature Communications

This method can be used to create not just one type of modified PEI but an entire library of modified polymers that can then be tested for cell toxicity and gene editing potential.

This library was then tested for genetic transformation efficiency in vitro on human cells.

Sumber: Nature Communications

Menemukan Polimer Pengantaran Gen Paling Efektif

Mengoptimalkan Struktur Polimer untuk Penyuntingan Gen

The research found there is a sweet spot regarding the mass of the polymer (molar mass): too high, and the mRNA is not released into the cell; too low, and particle stability was not good enough.

Other chemical characteristics proved beneficial, like a higher modification density, the presence of sufficiently hydrophobic groups, and tertiary amine groups.

This led to singling out a specific polymer formula with promising transfection performance, U155.

Sumber: Nature Communications

Nanopartikel U155 dalam Model Hewan Hidup

The next step was moving from cell cultures to a full organism, in this case, mice.

The efficiency of U155 was tested against a known in-vivo PEI-based gene editing procedure, JetPEI®, commercialized by Sartorius (SRT.DE).

“We demonstrate a multiple order increase of in vivo mRNA delivery to the lungs via systemic administration compared to the traditional PEI formulation standard.

The bioluminescence signal outperformed in vivo JetPEI® at the same dose (5 μg mRNA per mouse) by 50-fold.”

Once the general principle of U155 efficiency had been tested in vivo, the next step was to deploy it in a way that would mimic how a real gene therapy would work. Delivery to the lung, an organ notoriously difficult to treat with gene editing, was chosen.

U155 hybrid polymer-lipid nanoparticles, mixed with a chemical called DSPG and others were used to optimize the nanoparticles for conditions in the lungs.

Sumber: Nature Communications

“The pretreatment increased the expression in the lungs ∼2-fold compared to standard scheme.”

Tes Peradangan dan Toksisitas

Another critical step is being sure the new particles are not just efficient at gene editing in the lung, but safe and not causing unwanted side effects. Notably, acute lung inflammation is a known risk for such treatment.

Lung histological samples taken 24 h after 5ug nanoparticle injection, revealed no statistically significant difference in immune cell infiltration between U155 and PBS-injected animals and did not show signs of tissue damage.

Sumber: Nature Communications

Manfaat Terapeutik: Kanker Paru dan Fibrosis Kistik

If safe and performing gene editing, the logical conclusion is that such a product should be helpful for treating actual diseases. This was the next step checked by the researchers, using a mouse model of lung cancer, and delivery of a mRNA coding for the protein interleukin-12 (IL-12).

The mice injected with U155 demonstrated a much longer survival rate, and tumor growth significantly slowed down.

Sumber: Nature Communications

The treatment could also be repeated without negative side effects or loss of efficiency.

IL-12 cytokine concentration was approximately the same after the first and second doses, once again confirming the effectiveness of our platform for multiple dosage administrations.

Larger genetic sequences were also tested, in order to check the validity of this technology for a broader spectrum of possible gene editing.

The researchers notably checked for the delivery of CFTR mRNA (6132 b), a potential therapeutic approach for cystic fibrosis, a deadly genetic disease.

Not only was the gene expressed well in the treated mice, but the reactivity of the protein was also tested and improved by the treatment.

Sumber: Nature Communications

Lastly, U155 was also proved to deliver efficient CRISPR-Cas9 therapy to the lung and immune cells, demonstrating further the potential of these nanoparticles for gene editing.

Sumber: Nature Communications

Kesimpulan: Era Baru untuk Penyuntingan Gen Paru?

U155, and potentially other similar lipid nanoparticles, could be a game changer in gene editing for organs that have been so far hard to reach with gene editing technology.

Combined with the quick progress made in CRISPR technology and other gene editing methods, like mRNA technology, this could accelerate the trend of using gene therapy to permanently cure incurable diseases, instead of just treating the symptoms.

Most likely, the final point of these technologies is not only pinpoint accuracy regarding the section of the genome being edited but also customized nanoparticles adapted to each organ targeted and each genetic payload.

Berinvestasi dalam Penyuntingan Gen

Vertex Pharmaceuticals

Vertex is the leader in Cystic Fibrosis treatment, a deadly genetic disease, with 4 different treatments targeting different patient profiles. For patients who cannot be treated with the current therapies, Vertex has a drug in phase III of clinical trials, Vanzacaftor. They are also developing gene therapy for cystic fibrosis using mRNA technology.

The focus on lung diseases, especially cystic fibrosis, makes Vertex a company that could benefit greatly from better nanoparticles for lung gene editing.

As a whole, Vertex is very R&D-focused, with 70% of operating expenses and 3/5^th of the employees dedicated to finding new drugs and therapies.

It is now expanding quickly from a former startup and cystic fibrosis specialist to a strong rare disease-focused larger pharmaceutical company, notably kidney diseases.

Sumber: Vertex

Besides rare diseases, Vertex is also working on a type-1 diabetes therapy with its program called Zimislecel (formerly VX-880). The idea is to inject insulin-producing cells and use anti-rejection medication to ensure immune cells don’t attack transplanted cells.

A second approach encapsulates these same cells in a device to be surgically implanted in the body. These devices are designed with the aim of shielding the cells from the body’s immune system and removing the need for anti-rejection medication.

Vertex also saw its non-opioid pain medication Journavx approved in Januari 2025, with 20,000 prescriptions already filled 3 months later.

Sumber: Vertex

Vertex also owns the right to the commercialization and manufacturing of Casgevy, the world’s first approved CRISPR/Cas9 gene-edited therapy, developed in partnership with CRISPR Therapeutics (CRSP ). (Follow the link for a full report on CRISPR Therapeutics)

Vertex can rely on its stable income stream from its leading position in cystic fibrosis (a rare disease untreatable before Vertex’s success) to finance all of its expansion into new therapeutic fields.

It should also benefit from the recent approval of Exa-cel CRISPR gene therapy for blood diseases, Journavx for pain, and Zimislecel for diabetes.

In the long run, the biggest impact on the company finances will be from the potential commercial success of Journavx to reach the 80+ million potential patients, a type-1 diabetes permanent cure not requiring anti-rejection medication, together with a permanent gene editing cure for cystic fibrosis.

Berita dan Perkembangan Saham Vertex (VRTX) Terbaru

Studi yang Dirujuk

^{1. Vlasova, K.Y., Kerr, A., Pennock, N.D. et al.Sintesis lipopolimer ionizable menggunakan reaksi split-Ugi untuk pengantaran pulmonari berbagai ukuran RNA dan penyuntingan gen. Nat Communication16, 4021 (2025). https://doi.org/10.1038/s41467-025-59136-z}