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Gene Therapy for HoFH
What is homozygous familial hypercholesterolemia?
Individuals with familial hypercholesterolemia (FH) have very high blood levels of LDLcholesterol, or LDL-C, commonly known as “bad” cholesterol. The high levels of LDL-C lead to
deposition and buildup of cholesterol and plaque in the arteries, known as atherosclerosis, which
may lead to heart disease or stroke.1–6
Some individuals with FH have inherited a single copy of an FH disease-causing mutation from
one of their parents, leading to “heterozygous” FH (HeFH). For others, both parents have passed
on the FH mutation, which causes a more serious form of the disease, known as “homozygous”
FH (HoFH).2–6 Patients with HoFH have severely elevated LDL-C levels and develop early
cardiovascular disease, often in childhood. In the absence of aggressive treatment, many HoFH
patients suffer serious cardiac events before the age of 30.3–6
What causes “bad” cholesterol to accumulate in patients with HoFH disease?
In healthy individuals, LDL molecules are captured and broken down by the liver, preventing a
buildup of LDL-C in the blood. In patients with HoFH, however, this process is severely
compromised, allowing “bad” cholesterol to accumulate in the individual’s bloodstream. For many
individuals with HoFH, this is caused by an underlying genetic mutation that prevents the LDL
receptor (LDLR) on the surface of the liver from properly capturing and removing LDL from the
blood.3–6 In patients with HoFH, the LDLR can be either markedly defective or completely absent,
which may result in a range of residual LDLR activity and disease severity.
What are the current treatment options for HoFH and why do they fall short?
Some of the pharmacologic treatment options for reducing LDL-C, such as statins and the newly
approved PCSK inhibitors, work through increasing the levels of LDLR and therefore do not work
all that effectively in patients with HoFH in whom LDLRs are markedly impaired or absent. Two
other medications approved for HoFH reduce LDL-C by a mechanism separate from the LDLR,
but can increase fat in the liver.7 LDL apheresis has been used in patients with HoFH, but requires
prolonged weekly or biweekly visits. In severe cases of HoFH, particularly in children, liver
transplant has been used. At this time, none of the therapies available are able to restore LDLR
function as an approach to treat the disease.
What is gene therapy and how could it help patients with HoFH?
Gene therapy for HoFH attempts to treat the disease by delivering a normal, functional copy of
the LDLR gene into the patient’s own liver. With this healthy copy in place, the patient’s liver cells
could begin to make functional LDLR, allowing the liver to capture and break down LDL to
prevent the buildup of “bad” cholesterol.8
How does gene therapy work?
In order to deliver a healthy LDLR gene into a patient’s cells, gene therapy utilizes an engineered
virus as a delivery vehicle, or “vector.” The viral genes that cause infection are removed from the
vector and replaced by genes that enable the liver to make healthy LDLR without causing
toxicity. The outer shell of the vector acts like a vessel to transport the healthy LDLR gene into the
liver cells. Engineering the virus particle in this way ensures that the necessary gene is delivered
safely and efficiently to patient cells.
Might gene therapy for HoFH be effective?
Studies in animal models of HoFH have shown that a specific adeno-associated virus (AAV8)
vector carrying the LDLR gene can be delivered to the liver by injecting it into a vein.9–11 Delivering
the LDLR gene in this way resulted in an increase in LDL receptor levels in the animals, which
then markedly lowered the levels of LDL-C in the blood for a sustained period of time. These
results suggest that the approach to gene therapy for HoFH might be effective.
Is gene therapy safe?
Clinical trials of AAV vectors in patients with other diseases such as hemophilia have
demonstrated that gene therapy can be used safely in humans. For instance, vectors based on
the same delivery vehicle that will be used in the HoFH gene therapy clinical trials have been
well tolerated, and have shown evidence of effectiveness, in clinical studies of patients with
another genetic disease, hemophilia B.12 In addition, Glybera®, a gene therapy product using a
similar AAV vector, is currently approved for use in Europe for the treatment of another rare
disease, known as lipoprotein lipase deficiency.13 Upcoming clinical trials will assess possible
advantages and disadvantages of this approach in people with HoFH.
What is the future of gene therapy for HoFH?
Early experiments have shown that AAV8-based gene therapy for hemophilia can be effective
and last for several years.14 Upcoming clinical trials in patients with HoFH will evaluate both the
safety and effectiveness of this approach for treating this disease. The goal of gene therapy is to
offer a lasting, one-time treatment option to patients with HoFH. Future clinical studies will be
essential for determining the duration and extent of clinical benefit.
References:
1.
LDL & HDL: Good & Bad Cholesterol | cdc.gov. http://www.cdc.gov/cholesterol/ldl_hdl.htm.
Accessed August 10, 2015.
2.
Familial hypercholesterolemia: MedlinePlus Medical Encyclopedia.
http://www.nlm.nih.gov/medlineplus/ency/article/000392.htm. Accessed August 4, 2015.
3.
NIH-National Human Genome Research Institute. Learning About Familial
Hypercholesterolemia. https://www.genome.gov/25520184. Accessed August 4, 2015.
4.
Familial Hypercholesterolemia - NORD (National Organization for Rare Disorders).
http://rarediseases.org/rare-diseases/familial-hypercholesterolemia/. Accessed August 4,
2015.
5.
About HoFH - The FH Foundation. http://thefhfoundation.org/about-fh/homozygousfamilial-hypercholesterolemia/. Accessed August 13, 2015.
6. What is familial hypercholesterolemia? - Find out here. http://thefhfoundation.org/aboutfh/what-is-fh/. Accessed August 13, 2015.
7.
Rader DJ, Kastelein JJP. Lomitapide and mipomersen: two first-in-class drugs for reducing
low-density lipoprotein cholesterol in patients with homozygous familial
hypercholesterolemia. Circulation. 2014;129(9):1022-1032.
8. Kassim SH, Wilson JM, Rader DJ. Gene therapy for dyslipidemia: a review of gene replacement
and gene inhibition strategies. Clin Lipidol. 2010;5(6):793-809.
9. Kassim SH, Li H, Vandenberghe LH, et al. Gene therapy in a humanized mouse model of
familial hypercholesterolemia leads to marked regression of atherosclerosis. PloS One.
2010;5(10):e13424.
10. Kassim SH, Li H, Bell P, et al. Adeno-associated virus serotype 8 gene therapy leads to
significant lowering of plasma cholesterol levels in humanized mouse models of homozygous
and heterozygous familial hypercholesterolemia. Hum Gene Ther. 2013;24(1):19-26.
11. Lebherz C, Gao G, Louboutin J-P, Millar J, Rader D, Wilson JM. Gene therapy with novel
adeno-associated virus vectors substantially diminishes atherosclerosis in a murine model of
familial hypercholesterolemia. J Gene Med. 2004;6(6):663-672.
12. Nathwani AC, Tuddenham EGD, Rangarajan S, et al. Adenovirus-associated virus vectormediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357-2365.
13. Glybera EMA Product Information. Amsterdam, The Netherlands: uniQure biopharma B.V.;
2015.
14. Buchlis G, Podsakoff GM, Radu A, et al. Factor IX expression in skeletal muscle of a severe
hemophilia B patient 10 years after AAV-mediated gene transfer. Blood. 2012;119(13):3038-3041.