In Vivo

Our first wave of in vivo gene editing programs aims to provide one-time treatments that could permanently reduce the burden of heart disease

Extending the frontier of gene editing with in vivo approaches

We are building on the expertise we have gained through our ex vivo programs to advance our portfolio of in vivo programs across both rare and common diseases. We believe that delivering gene editing cargo either systemically or into specific target organs in the body has the potential to address a variety of diseases.

Non-viral and viral approaches to in vivo delivery

Currently, several methods exist to deliver DNA or RNA to cells inside the body, which we can adapt to deliver gene editing components. These methods fall into two broad categories: non-viral and viral. We are developing therapeutic programs based on technologies in both these areas.

Non-viral: Our efforts into non-viral delivery methods have focused on lipid nanoparticles (LNPs), which predominantly target the liver. We can encapsulate messenger RNA (mRNA) encoding Cas9 and guide RNA into LNPs that are designed to shuttle these components to the liver.

Viral: For other organ systems, including the muscle, lung and central nervous system, we have emphasized viral delivery, primarily using adeno-associated viral (AAV) vectors. These vectors are designed to deliver DNA encoding for Cas9 and guide RNAs into specific tissues of the body.

Our first in vivo programs target validated genes that have a known association with cardiovascular disease. These programs use lipid nanoparticles (LNPs) to deliver Cas9 mRNA and gRNA to the liver with the goal of reducing expression of Lp(a) and ANGPTL3, respectively.

Lp(a)

Lp(a) is a type of “bad cholesterol” that is a risk factor for several types of cardiovascular disease including atherosclerosis and calcific aortic valve disease.

  • Lp(a) is made in the liver and transports cholesterol, a fatty substance that, when in excess, builds up as plaque inside blood vessels. Plaque buildup can make blood vessels too narrow for blood to flow freely. This condition is called atherosclerosis and increases the risk of heart attack, stroke, and other cardiovascular problems.
  • Lp(a) can also lead to inflammation, causing thickening or hardening of arteries or stiffening of valves that control blood flow in the heart, which can lead to aortic valve disease.

High levels of Lp(a) are mostly determined by your genes that you inherit from parents. Unlike other types of bad cholesterol, Lp(a) cannot be lowered much by diet and lifestyle changes.1

Previous studies have shown that people born with very low levels of Lp(a) had a decreased risk of developing heart disease.2 There are no known risks associated with having low Lp(a) or no Lp(a).3

ANGPTL3

ANGPTL3 is a protein made in the liver that may contribute to increased levels of cholesterol and triglycerides, leading to increased plaque in the arteries. This plaque increases the risk for cardiovascular diseases and major cardiovascular events such as heart attacks and strokes.4

There have been people born without ANGPTL3 – these people have reduced cholesterol and triglycerides and they have decreased risk of cardiovascular events. There are no known risks associated with having no ANGPTL3.5

References:
  1. Luo F, et al. Trends Cardiovasc Med. 2024; doi: 10.1016/j.tcm.2023.01.008.
  2. Kyriakou T, et al. Arterioscler Thromb Vasc Biol. 2014; doi: 10.1161/ATVBAHA.114.303462.
  3. Schmidt K, et al. J Lipid Res. 2016; doi: 10.1194/jlr.R067314.
  4. Gallone G, et al. JACC Cardiovasc Imaging. 2023; doi: 10.1016/j.jcmg.2023.08.006.
  5. Minicocci I, et al. J Clin Endocrinol Metab. 2012; doi: 10.1210/jc.2012-1298.

To learn more about the full range of investigational therapies we are developing, visit our pipeline page.

Pipeline

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