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Lipid Nanopartiküller Akciğer Gen Düzenlemesini Kolaylaştırıyor

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Lipid Nanopartiküller Akciğer Gen Düzenlemesini Nasıl Etkinleştiriyor

Recently, some advanced gene editing therapies have been approved, özellikle orak hücre hastalığı gibi kan hastalıkları için. In theory, this opens the door to a lot more gene therapies, especially for rare and/or incurable diseases.

Pratikte, bu kadar basit değil, çünkü gen düzenleme teknolojisinin önce doğru organlara ulaşması ve organın yeterli sayıda hücresinin değiştirilebilmesi için yeterince yüksek bir dönüşüm oranına sahip olması gerekir. Bu, gen terapilerini geliştirmenin başka bir yolunun daha iyi gen düzenleme sistemleri (ör. CRISPR) değil, gen düzenleme ürününün daha iyi taşıma sistemleri olması anlamına geliyor.

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 “Split-Ugi reaksiyonu kullanılarak iyonlaşabilir lipopolimerlerin sentezi ve çeşitli boyutlardaki RNA’ların pulmoner teslimatı ile gen düzenleme”.

Gen Tesliminde Karşılaşılan Zorluklar ve Yaklaşımlar

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:

  • Genetik materyalin hücre çekirdeğine entegre edilmesindeki zorluklar.
  • Genin eklenmesini hedeflemedeki zorluklar, istenmeyen mutasyonlara ve öngörülemeyen gen ekspresyon seviyelerine yol açar.
  • Genetik materyalin hücre zarından geçmesini sağlamakla ilgili sorunlar.

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.

Genetik materyalin teslimatı çözülmesi daha zor bir sorun olmuştur. Tarihsel olarak, modifiye viral parçacıklar veya elektrik şoku hücreyi değiştirmek için kullanılmıştır.

Daha modern bir yaklaşım, tedaviyi kapsülleyen mühendislik lipid parçacıkları kullanmaktır; çünkü bu parçacıklar hücre zarıyla birleşme yeteneğine sahiptir. Bu, Covid pandemisi sırasında kullanılan mRNA aşılarının mRNA yüklerini teslim etme şekli olarak öne çıkmaktadır.

Bu parçacıklar ayrıca mRNA moleküllerini sistemik dejenerasyondan koruyan ve endozomdan kaçışını kolaylaştırarak hücre içinde fonksiyonel proteinlere verimli bir şekilde çevrilmesini sağlayan kimyasal motifler içermelidir.

Şu ana kadar, her yeni terapi için özgün teslimat yöntemleri mühendislik edilmekte, belirli bir mRNA veya DNA boyutuna, hedef hücrelere ve organizmaya göre optimize edilmektedir. Bu durum, yeni terapilerin geliştirilmesinde bir engel olmuş ve yeni tedavilerin onay sürecinde büyük bir düzenleyici yük oluşturmuştur.

Daha Güvenli Gen Teslimi İçin Yeni Bir Polimer Kimyası

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.

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.

En Etkili Gen Teslim Polimerlerini Keşfetmek

Gen Düzenleme İçin Polimer Yapısını Optimize Etmek

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.

Canlı Hayvan Modellerinde U155 Nanopartiküller

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.

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

İnflamasyon ve Toksisite Testleri

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.

Terapötik Faydalar: Akciğer Kanseri ve Kistik Fibroz

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.

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.

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.

Sonuç: Akciğer Gen Düzenlemesi İçin Yeni Bir Dönem mi?

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.

Gen Düzenlemesine Yatırım

Vertex Pharmaceuticals

(VRTX )

Vertex, ölümcül bir genetik hastalık olan kistik fibroz tedavisinde lider konumda olup, farklı hasta profillerine yönelik 4 farklı tedavi sunmaktadır. Mevcut terapilerle tedavi edilemeyen hastalar için Vertex, klinik denemelerin III. fazında Vanzacaftor adlı bir ilaç geliştirmektedir. Ayrıca mRNA teknolojisi kullanarak kistik fibroz için gen terapisi geliştirmektedir.

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 3/5i 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.

Vertex'in hastalık tipine göre ilaç geliştirme odakları

Kaynak: 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 opioidsiz ağrı ilacı Journavx approved in Ocak 2025, with 20,000 prescriptions already filled 3 months later.

Vertex tedavilerinin pazar fırsatı ve geliştirme aşaması

Kaynak: 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 ). (CRISPR Therapeutics hakkında tam rapor için bağlantıyı takip edin)

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.

En Son Vertex (VRTX) Hisse Senedi Haberleri ve Gelişmeler

Referans Çalışma

1. Vlasova, K.Y., Kerr, A., Pennock, N.D. et al.Synthesis of ionizable lipopolymers using split-Ugi reaction for pulmonary delivery of various size RNAs and gene editing. Nat Communication16, 4021 (2025). https://doi.org/10.1038/s41467-025-59136-z 

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Jonathan eski bir biyokimya araştırmacısıdır ve genetik analiz ve klinik çalışmalar üzerinde çalışmıştır. Şimdi bir hisse analisti ve finans yazarıdır ve yayınında 'The Eurasian Century' da inovasyon, piyasa döngüleri ve jeopolitika üzerine odaklanmaktadır.