Gene Therapy: Hope for Rare Diseases

  • Elena Paspel Master of Science in Engineering (Digital Health) - Tallinn University of Technology, Estonia
  • Helen McLachlan MSc Molecular Biology & Pathology of Viruses, Imperial College London

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From birth, Megan faced significant struggles. She was unusually weak, and unable to move her head or limbs properly. At only three months old, she was diagnosed with spinal muscular atrophy (SMA). This rare genetic disorder, caused by a mutation in the SMN1 gene, leads to the loss of motor neurons and muscle wasting. Without treatment, children with SMA, like Megan, typically don't survive past early childhood.

Megan's parents were initially devastated. But hope came when their doctor mentioned a new gene therapy. This cutting-edge treatment involved putting a healthy SMN1 gene into Megan's motor neurons, using a modified virus vector for delivery​​. A one-time infusion could potentially maintain her muscle function. This therapy was Megan's best chance for a normal life.

Megan received gene therapy at five months old. While she still needs ongoing care, she recently celebrated her third birthday. This was a remarkable achievement, considering the prognosis for SMA a decade ago. Megan's story is a powerful example of how gene therapy can change the lives of those with rare genetic disorders.

Gene therapy: a basic overview

Gene therapy treats genetic diseases by either replacing a bad gene or adding a new one into a person's cells.1 This is often done using special virus vectors. These are viruses changed to carry normal genes into cells safely. The viruses often used are adenoviruses and adeno-associated viruses (AAVs)​.1 

The DNA or RNA of the needed gene is put into the virus vector.1 The virus then carries this genetic material to the cells that need it. Once inside, the new gene can help compensate for the one that is missing or defective.1 

Gene therapy is given in two ways. Ex vivo therapy involves changing cells in a lab and then putting them back in the body. In vivo therapy means injecting the therapy directly into the patient.1 The method used depends on the disease, and the tissues targeted.

Gene therapy for rare diseases

Initially, gene therapy targeted common diseases like cystic fibrosis. Today, it offers hope for treating over 7,000 rare diseases. These affect more than 25 million people in the USA.1-2 Often, these rare diseases have limited treatment options. Gene therapy can correct the genetic issues at their root, ideally leading to lasting benefits from just one treatment.

This therapy has made progress in treating various diseases. These include ones that affect the eyes, brain, muscles, blood, and liver. Conditions like spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD), haemophilia, and some eye disorders have seen positive results.1-2 Often, a single treatment can greatly improve movement, brain function, or vision. Without this, patients may face shorter lives and disability.

Gene therapy's role in treating spinal muscular atrophy (SMA)

Spinal muscular atrophy (SMA) is a distressing disease that mostly affects children. It weakens their muscles, making basic movements difficult. SMA happens due to an issue in the SMN1 gene, which is vital for muscle movement. Thankfully, gene therapy offers significant hope in treating this condition.

Gene replacement therapy: a new hope

Gene replacement therapy can substitute the defective gene causing SMA. This therapy introduces a healthy SMN1 gene using a safe, modified virus, called Onasemnogene abeparvovec. Treatment with this therapy has been effective, and treated infants have shown improved skills, like sitting alone, and better survival rates. However, there are challenges. Early treatment is crucial, and there are concerns about liver safety and the therapy's high cost.3

Antisense oligonucleotide (ASO) therapy

Antisense oligonucleotide (ASO) therapy uses a unique method. It doesn't change the gene but fine-tunes it to work more effectively. This method uses small pieces of genetic material to modify the processing of the SMN2 gene, a backup gene, to produce more functional protein. Nusinersen is one such drug that has significantly improved the life expectancy of children with SMA1.3

Small-molecule modulators: pills with potential

These are oral medications that, like ASO therapy, enhance the backup SMN2 gene's function. Risdiplam is a notable example that has shown improvements in motor functions in clinical trials. This oral medication offers an easier administration route compared to the intrathecal injections required for ASO therapy.3

Gene therapy for haemophilia

Haemophilia is a disease where blood doesn't clot properly, causing too much bleeding. Traditional treatments need regular blood infusions, which are costly and complicated. Gene therapy offers a new solution.

A one-time treatment

In gene therapy, patients get a single treatment. This introduces a fixed version of the gene needed for clotting,using adeno-associated viral (AAV) vectors. These have been effective in trials, reducing bleeding in haemophilia patients. However, as of 2023, only adult men with severe haemophilia and no advanced liver disease have been tested.4

Challenges in implementation

There are hurdles in using gene therapy for haemophilia. If patients already have antibodies against the AAV vector, the treatment might not work well. Also, keeping the clotting factor at the right level over time is key to avoid problems like blood clots​.4

The future of haemophilia treatment

The outlook for treating haemophilia with gene therapy is hopeful. It could offer a lasting solution, but more research and trials are needed to improve these therapies. They must be safe, effective, and easy to access.4

Gene therapy and ALS

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, severely affects muscle control. Gene therapy is emerging as a promising treatment, offering hope where other treatments haven't.

Understanding ALS and its treatment

ALS destroys neurons that control voluntary muscles. Gene therapies target these genetic problems. Strategies include antisense oligonucleotides (ASOs) for gene silencing, RNA interference, and CRISPR for gene editing, aiming to introduce, modify, or silence genes associated with ALS.5

Current developments in ALS gene therapy

Recent advances have seen trials using ASOs to target genes like SOD1, which are linked to familial forms of ALS. In these trials, ASOs are delivered directly into the central nervous system, showing promise in reducing disease progression. Another approach uses adeno-associated virus (AAV) vectors to deliver therapeutic genes or silence harmful ones. These vectors are chosen for their ability to target specific cells and provide long-term treatment effects.5

Challenges and future directions

The variability in ALS's genetic causes necessitates potentially personalised treatments. Delivering therapy effectively to all affected neurons in the brain and spinal cord is a major challenge in this field.5

Hope in ALS research through gene therapy

Ongoing research in ALS gene therapy is inspiring hope for those affected. With more progress, this therapy might soon greatly slow or even stop ALS. This could change ALS from a fatal condition to one that can be managed.5

Gene augmentation for sphingolipidoses

Sphingolipidoses are rare genetic diseases caused by enzyme mutations. These lead to harmful substance buildup in cells, mainly harming the nervous system. Gene augmentation therapy introduces healthy genes to make these missing enzymes.

Progress in treating sphingolipidoses

Recent advances in gene therapy are using adeno-associated viral (AAV) vectors. These are being developed to treat various types of sphingolipidoses. AAV vectors are preferred due to their ability to target specific cells, and for their safety profile. They have been explored in various clinical settings to deliver therapeutic genes effectively, showing promise in managing these complex conditions.6

Challenges in sphingolipidoses treatment

Gene augmentation therapy brings hope for sphingolipidoses, but challenges exist. Personalised treatment is crucial due to genetic diversity. Researchers focus on ensuring effective delivery and lasting effects in their studies and trials.6

Gene therapy in Duchenne muscular dystrophy (DMD)

Duchenne muscular dystrophy (DMD) causes progressive muscle loss, due to DMD gene mutations affecting dystrophin production, essential for muscles. Gene therapy aims to correct this genetic issue.

CRISPR-Cas9 in DMD treatment

CRISPR-Cas9 technology is a breakthrough in DMD therapy. It edits the DMD gene to restore dystrophin and stop muscle loss. This has shown promise in early trials​.7

However, challenges like precise editing and potential side effects remain. Ongoing research is vital to improve these therapies for DMD patients​.7

Gene therapy for cystinuria

Cystinuria leads to kidney stones due to excessive cystine, caused by mutations in specific genes. Gene therapy aims to fix these mutations. Researchers use viral vectors, like AAVs, to deliver corrected genes to kidneys. This could replace current treatments .8

While promising, gene therapy for cystinuria faces challenges in ensuring effective delivery and expression of therapeutic genes.8

Treating IPEX syndrome with gene therapy

IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome is a severe autoimmune disorder caused by FOXP3 gene mutations. This affects regulatory T cells. Gene therapy focuses on fixing or replacing the FOXP3 gene

FOXP3 Gene Correction

FOXP3 Gene Correction uses tiny tools called lentiviral vectors. These act like mini trucks, carrying the FOXP3 gene into the body. Once inside, the gene acts as a guide for making the FOXP3 protein.9 This protein is crucial for health.

The main aim of this method is to fix regulatory T cells. By delivering a working FOXP3 gene with these vectors, scientists hope to treat IPEX syndrome. Clinical trials are testing how safe and effective this approach is.9

CRISPR/Cas9-based gene editing: Precision and promise

Another promising technique involves CRISPR-Cas9 gene editing. CRISPR-Cas9 offers precise correction of the FOXP3 gene. This ensures the regulation and function of regulatory T cells, offering hope for long-term relief from IPEX symptoms​.9

Gene therapy for retinal degeneration

A rare retinal degenerative disease, retinitis pigmentosa, causes vision loss. Gene therapy targets the genetic causes.

This therapy uses vectors, such as AAVs, to deliver a healthy copy of the RPE65 gene directly to retinal cells. It aims to replace or repair genes causing retinal degeneration. An example is voretigene neparvovec, an FDA-approved drug for certain retinitis pigmentosa forms. Researchers are working to improve long-term effectiveness and address various genetic causes.10

Challenges and future outlook

Though great progress has been made, delivering genes safely and getting them to function properly remains technically challenging. Potential side effects like the activation of an oncogene or immune reactions to the viral vector must also be managed.2 And with price tags upwards of $2 million per treatment, cost and insurance coverage are additional barriers.

However, with recent approvals of pioneering gene therapies like Onasemnogene abeparvovec for SMA, the field is rapidly advancing. Improved viral vectors, innovative delivery methods, and combination gene and drug therapies are areas of active research.1 Gene editing technologies like CRISPR may also open up new possibilities. If challenges can be overcome, gene therapy could offer life-changing hope for the millions suffering from rare genetic conditions worldwide.


Gene therapy is a major breakthrough in rare disease treatment, bringing hope. It's effective in diseases like SMA, ALS, Duchenne muscular dystrophy, and retinal degeneration. Real-world breakthroughs in haemophilia and other diseases highlight its impact. Still, there are challenges with safety, results, and getting access. Ongoing research and development will keep improving gene therapy. It's changing the way we treat rare diseases, giving hope to many.


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  • Arabi F, Mansouri V, Ahmadbeigi N. Gene therapy clinical trials, where do we go? An overview. Biomedicine & Pharmacotherapy [Internet]. 2022 Sep 1 [cited 2024 Jan 11];153:113324. Available from: 
  • Ponomarev AS, Chulpanova DS, Yanygina LM, Solovyeva VV, Rizvanov AA. Emerging gene therapy approaches in the management of spinal muscular atrophy (Sma): an overview of clinical trials and patent landscape. International Journal of Molecular Sciences [Internet]. 2023 Sep [cited 2024 Jan 11];24(18). Available from: 
  • Samelson-Jones BJ, George LA. Adeno-associated virus gene therapy for hemophilia. Annual review of medicine [Internet]. 2023 Jan 1 [cited 2024 Jan 11];74:231. Available from:
  • Amado DA, Davidson BL. Gene therapy for ALS: A review. Mol Ther [Internet]. 2021 Dec 1 [cited 2024 Jan 11];29(12):3345–58. Available from: 
  • Shaimardanova AA, Solovyeva VV, Issa SS, Rizvanov AA. Gene therapy of sphingolipid metabolic disorders. Int J Mol Sci [Internet]. 2023 Feb 11 [cited 2024 Jan 11];24(4):3627. Available from: 
  • Happi Mbakam C, Lamothe G, Tremblay G, Tremblay JP. Crispr-cas9 gene therapy for duchenne muscular dystrophy. Neurotherapeutics [Internet]. 2022 Apr [cited 2024 Jan 11];19(3):931–41. Available from: 
  • Peek JL, Wilson MH. Gene therapy for kidney disease: targeting cystinuria. Curr Opin Nephrol Hypertens [Internet]. 2022 Mar 1 [cited 2024 Jan 11];31(2):175–9. Available from: 
  • Borna S, Lee E, Sato Y, Bacchetta R. Towards gene therapy for IPEX syndrome. Eur J Immunol [Internet]. 2022 May [cited 2024 Jan 11];52(5):705–16. Available from:
  • Drag S, Dotiwala F, Upadhyay AK. Gene therapy for retinal degenerative diseases: progress, challenges, and future directions. Invest Ophthalmol Vis Sci [Internet]. 2023 Jun 30 [cited 2024 Jan 11];64(7):39. Available from:

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Elena Paspel

Master of Science in Engineering (Digital Health) - Tallinn University of Technology, Estonia

Bachelor of Laws - LLB (Hons), London Metropolitan University, UK

An experienced professional with a diverse background spanning law, pricing, and eHealth/Digital Health. Proficient in copywriting, medical terminology, healthcare interoperability standards, and MedTech regulations. A strong foundation in scientific research methodologies and user experience research supports the creation of compelling content for the biopharmaceutical, CROs, medical technology, and eHealth sectors.

Proven expertise in driving product vision, synthesizing complex information, and delivering user-centric solutions. Adept at streamlining workflows and processes, and drafting documentation and SOPs. Always open to collaborations and eager to connect with like-minded professionals.

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