Homozygous Familial Hypercholesterolemia (HoFH)
Homozygous familial hypercholesterolemia (HoFH) is a rare but serious genetic disorder that results in extraordinarily high levels of low-density lipoprotein cholesterol (LDL-C) in the bloodstream. Our company specializes in providing a robust suite of comprehensive, one-stop services tailored for researchers and scientists dedicated to the study of rare diseases, including HoFH.
Overview of HoFH
HoFH is defined by its autosomal dominant pattern of inheritance, which leads to important atherosclerotic disease at a young age owing to prominent defects in the LDL receptor (LDLR) pathway. The prevalence of HoFH ranges between 1 in 300,000 and 1 in 360,000 individuals. It is significantly more severe than its counterpart, heterozygous familial hypercholesterolemia (HeFH), and has a greatly elevated risk of developing cardiovascular disease at a premature age.
Fig.1 Step-by-step HoFH therapy algorithm. (Kayikcioglu, M., and Tokgozoglu, L., 2022) Pathogenesis of HoFH
The core of HoFH stems from a disruption in the LDLR gene, which is sustained mainly by mutations but also by defects in genes such as APOB and PCSK9. The LDLR gene is essential in regulating the extraction of LDL-C out of circulation. Its abnormality causes a dramatic decrease or total absence of receptor-mediated activity. As a consequence, the diminished metabolic clearance of LDL-C results in its hypercholesterolemic deposition in various tissues. Such tissues gradually accumulate within the arterial walls, which fosters the development of atherosclerotic plaques.
Fig.2 Lipid lowering agents used for HoFH therapy and their mode of action. (Kayikcioglu, M., and Tokgozoglu, L., 2022)Diagnostics Development of HoFH
Finding and validating diagnosis of HoFH is highly dependent on genetic testing. It confirms mutation in genes responsible for the metabolism of LDL-C, such as LDLR, APOB, and PCSK9. The identification of these mutations enables the physician to determine the prognosis, direct therapy, and evaluate the degree of cardiovascular complications.
Therapeutics Development of HoFH
| Agents | Types | Mechanism of Action | Targets | Research Phase |
|---|---|---|---|---|
| Alirocumab | Monoclonal antibody | Inhibits PCSK9 | PCSK9 | Approved |
| Evinacumab | Monoclonal antibody | Monoclonal antibody to ANGPTL3 | ANGPTL3 | Approved |
| Ezetimibe | Small molecule drug | Inhibits NPCILI protein | NPCILI | Approved |
| Lomitapide | Small molecule drug | Inhibits MTP, thereby interfering with the assembly of lipoproteins | MTP | Approved |
| Mipomersen | Small molecule drug | A second-generation antisense oligonucleotide (ASO) inhibitor targeting ApoB | ApoB | Approved |
| Inclisirian | Small interfering ribonucleic acid | SiRNA inhibiting the translation of PCSK9 | PCSK9 | Approved |
| ARO-ANG3 | Small interfering ribonucleic acid | A siRNA targeting the ANGPTL3 gene | ANGPTL3 | Phase II trials |
| Lerodalcibep | Recombinant fusion protein | Suppress PCSK9 and LDL-C | PCSK9 / LDL-C | Phase III trials |
Our Services
Supporting research by providing full-range pet services on a rare disease basis as well as building a collaborative network for animal models and developing therapeutic is the core mission of our company.
Therapy Development Platforms
Animal Models of HoFH
To comprehend the nuances of inherited metabolic defects, animal models serve as a great resource with respect to studying any aspect of the disorder. Apart from elucidating particular areas of interest, developing effective therapeutics for HoFH also hinges on good animal models. Our company offers a range of animal models for the investigation of the disease progression and the effects of therapeutic.
HoFH-like phenotypes have been induced in animals through gene editing techniques, targeting LDLR or other genes involved in cholesterol metabolism.
Optional Models: Ldlrtm1Her model; Apobtm2Sgy model; Pcsk9tm1Jdh model, etc.
Why Choose US
We are dedicated to supporting researchers and scientists in their pursuit of scientific excellence and improving the lives of individuals affected by HoFH.
If you want to learn more about our services and how we can support your research endeavors, please do not hesitate to contact us for further information.
References
- Kayikcioglu, Meral, and Lale Tokgozoglu. "Current Treatment Options in Homozygous Familial Hypercholesterolemia." Pharmaceuticals (Basel, Switzerland) 16.1 (2022): 64.
- Nohara, Atsushi et al. "Homozygous Familial Hypercholesterolemia." Journal of atherosclerosis and thrombosis 28.7 (2021): 665-678.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.