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In recent years, there has been increasing news about the entry of various gene therapy treatments into clinical trials. Rare disease, as one of the most easily cure diseases by gene therapy, the research and development of gene therapy drugs for most monogenic rare diseases has also made important progress.

The World Health Organization (WHO) defines rare diseases as diseases with a total population of 0.65-1 %. Due to a low incidence rate, rare diseases are also known as "orphan diseases", and the corresponding drugs are called orphan drugs. Although the number of patients with each disease is small, the total number of rare disease patients is very large due to the wide variety of diseases. There are more than 300 million patients living with rare diseases in the world. Thus, it is of great significance to develop treatments for rare diseases.

Since about 80% of the rare diseases are caused by gene mutation, they are ideal targets for gene therapy treatment. This article will introduce the current research progress and case analysis of gene therapies for rare diseases.


What is Adeno-Associated Virus (AAV)-based Gene Therapy?

The process of gene therapy involves first identifying the target gene, then using a vector to carry the targeted gene into the body. Currently, viral vectors are the most used, with early clinical trials using retroviruses, lentiviruses, adenoviruses, etc. However, because of their limitations and safety risks, these traditional viruses have been gradually replaced by adeno-associated viruses (AAV). Adeno-associated virus (AAV) is regarded as the most promising viral vector for gene therapy applications due to its high safety and stable long-term expression.


Case studies: AAV-based Gene Therapy in Rare Diseases

Duchenne muscular dystrophy (DMD) is a rare and fatal neuromuscular genetic disease affecting approximately 1 in 3,500 male births worldwide. The symptoms usually appear in infancy, and muscle weakness occurs at the age of 4 and worsens rapidly. Most patients lost their walking ability before 12 years old. Finally, dyspnea is aggravated due to respiratory muscle dysfunction, which requires ventilation support and cardiac dysfunction can lead to heart failure. The disease is fatal, and patients have an average life expectancy of 26. At present, there is no cure for DMD, treatment options aim to improve some symptoms with physical therapy and corrective surgery.

The main cause of DMD is a mutation in the gene encoding dystrophin, which is very important for maintaining the cell membrane of muscle fibers. Therefore, gene therapy is considered an ideal treatment option with the potential to cure the disease. Pf-06939926 is a gene therapy treatment under development by Sarepta therapeutics, this therapy can transfer the "mini dystrophin" gene controlled by human muscle-specific promoter into adeno-associated virus 9 (AAV9) vector, which is then injected into the patient’s body. By transfecting the muscle cells of the patients, it allows the muscle to produce a recombinant protein with partial dystrophin function to alleviate the disease progression of DMD patients.

The advantage of this gene therapy is that it can be effectively targeted for patients with any type of DMD gene mutation. The AAV9 virus vector can target delivery of the transgene to muscle tissue, confirming the ability of AAV9-mediated gene therapy to transfect muscle tissue.


Case 2: Gene Therapy for Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA) is a rare hereditary neuromuscular disease. SMA can cause rapid and irreversible loss of motor neurons, affecting muscle function, including breathing, swallowing, and basic movement. Although the incidence rate is about 1/10000, the disease is highly lethal; even with treatment, most children will not survive to 20 months.

The main cause of SMA is that patients have a loss of function of the coding gene SMN-1, which encodes an abnormal SMN protein - which is essential for the survival of motor neurons. Without a functioning SMN protein, neurons cannot work normally, leading to muscle weakness and sluggishness. The disease can be divided into five types, although two of these – Type 0 and Type 4 – are exceedingly rare, accounting for less than 1% of all diagnosed cases. The three most prevalent types are: delayed-type SMA-2, SMA-3, and the most common SMA-1, which accounts for about 60% of all cases.

Zolgensma (onasemnogene abepalvovec) was approved and became the first gene therapy for SMA in the world. The vector for this drug employs an adeno-associated viral vector (AAV) type 9 (AAV9), because AAV9 type viral vectors can penetrate the blood-brain barrier. The drug can prevent disease progression by continuously expressing SMN protein after a single, one-time intravenous (IV) infusion, which can solve the fundamental cause of SMA and is expected to improve the patient’s quality of life in the long term.【2】


Case 3: Gene Therapy for Leber Congenital Amaurosis (LCA)

Leber congenital amaurosis (LCA) is a severe and early-onset hereditary retinopathy that is the most common cause of inherited blindness. LCA is inherited in an autosomal recessive manner. The prevalence of LCA worldwide is estimated to affect as many as 1 in 50,000-100,000 people, accounting for 5% of hereditary retinal degeneration and 10% - 20% of congenital blindness in children.

At present, 27 kinds of LCA pathogenic genes have been identified, and patients with mutations in these genes account for more than 70% of all LCA patients. Among these, Leber's congenital amaurosis type 1 (LCA1) is caused by a mutation of the GUCY2D gene, which can lead to early and severe visual impairment or blindness. The LGUCY2D gene is located on human chromosome 17, at position 17p13.1, and its coding product is guanylate cyclase 1 (retGCl, GC1). GC1 is a transmembrane protein, which is specifically expressed in the nuclei and inner segments of retinal cones and rod cells. When the GUCY2D gene is mutated, it is equivalent to giving continuous light stimulation to the photoreceptor cells during the development stage, resulting in a situation similar to photoreceptor apoptosis from continuous light irradiation.

In one study of eye genetic diseases, Boyce et al. used a guanylate cyclase-1 (GC1) gene knockout mouse model to conduct research. They found that the GC1 gene is closely related to the onset and pathogenesis of Leber congenital amaurosis (LCA). When the GC1 gene was deleted, the damage in cone cells was similar to LCA; However, the function of damaged cone cells can be partially restored by using an AAV vector to make the GC1 gene overexpressed continuously. This provides a new idea for the treatment of this hereditary disease【3】


Cyagen One-stop Solution for Rare Disease Drug Development

More than 80% of rare diseases are caused by specific gene mutations. Generally speaking, there are hundreds of gene mutations associated with each disease. Developing the desired animal research model via gene-editing technology requires extensive identification and phenotype analysis efforts. However, rare diseases historically have less than a 15% probability of successfully recapitulating the human phenotype in mouse models. This has posed a huge challenge for rare disease drug research & development worldwide.

As a leading provider of custom mouse and rat models, Cyagen aims to support the advancement of rare disease and related gene therapy research with our expertise. Cyagen is committed to enabling development of therapeutics for rare diseases by developing precise animal models to study disease mechanisms, target validation, drug screening and more.

Based on Cyagen’s innovative technology, our team can rapidly construct various types of genetically modified mouse models including gene knockout, conditional knockout, humanization, point mutation, and more. We can create any custom mouse or rat model with guaranteed genotype validation along with phenotype analysis and other downstream services to establish an accurate rare disease model. In addition, we have established a drug screening animal platform for cancer, immunology, endocrinology, cardiovascular, neurology, and infectious diseases. This platform provides high-quality and stable animal models services to support drug efficacy evaluations for CRO institutions and drug R&D institutions to accelerate the progress of drug development. In addition to the construction of mouse models, we also have rich expertise in rat model construction. So far, we have delivered over 78,400 murine models to researchers worldwide and received over 4,750 peer-reviewed citations for our products and services. Cyagen prides itself on its premium customer service: including price-matching, client access to complimentary technical consultations, full confidentiality, and a 100% money-back service guarantee.


Cyagen One-Stop Gene Therapy Model Solutions

Cyagen provides comprehensive model generation services for all your research needs. Contact us to perform your entire project - from initial strategy design and experimental model construction, all the way through supporting services – we deliver research-ready models and professional services for guaranteed results.




  • Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723-1732.
  • Boye SE, Boye SL, Pang J, Ryals R, Everhart D, Umino Y, Neeley AW, Besharse J, Barlow R, Hauswirth WW. Functional and behavioral restoration of vision by gene therapy in the guanylate cyclase-1 (GC1) knockout mouse. PLoS One. 2010;5(6):e11306. DOI: 10.1371/journal.pone.0011306. PMID: 20593011; PMCID: PMC2892468.
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