A spotlight on gene therapies for neurological diseases

Gene therapies offer a new frontier for many neurological diseases. Addressing the treatment challenges posed by conditions such as Duchenne muscular dystrophy (DMD) could provide targeted therapy with a durable treatment response. This industry update session at ANA Virtual 2022 shone a spotlight on recent developments.

What is gene therapy?

The aim of gene therapy, said Dr Sandra Reyna (Novartis Gene Therapies), is to introduce or modify genetic material in an individual to achieve a therapeutic objective1.  It is an innovative treatment approach for monogenic diseases caused by mutations or overexpression of a single gene1. The genetic material or modifier is introduced into the target cell using a viral or non-viral vector, resulting in increased/decreased protein expression or production of a modified protein1.

An innovative treatment approach for monogenic diseases caused by mutations or overexpression of a single gene

There has been rapid growth in gene therapies since the first retroviral vector was approved in 1989 for gene transfer into humans2. An important development has been discovering the underlying genetic cause of several neurological diseases. After oncology, neurological diseases are one of the most common targets for gene therapies3.


Use of viral vectors

Currently, 88% of gene therapies in development use viral vectors, with adeno-associated virus (AAV) and lentivirus the most common3. Dr John Kincaid (Novartis Gene Therapies) discussed how viral vectors are either injected directly into the target tissue or used to modify the patient’s cells in culture followed by re-injection of cells into the patient4. Each viral vector has a different benefit-risk profile. AAV vectors have a low risk of genomic integration and are naturally non-pathogenic but limited by a small packaging capacity5.


Clinical development

Prof Arthur Burghes (Ohio State University, USA) focused on AAV vectors which display broad tropisms specific to tissue types6. It is possible to engineer unique capsids to target a particular tissue, eg, skeletal muscle for a muscle disease. Biodistribution can vary across different species as well as tissue types, which needs to be considered when using results from animal models7.

It is possible to engineer unique capsids to target a particular tissue

Vector efficacy may be affected by anti-AAV neutralizing antibodies, which are often lower in younger individuals8. Even vectors that have been designed to not integrate with the host have a potential risk of integration. This has been low for AAV vectors in preclinical studies and reduces their oncogenic potential9.


Use in neurological diseases

Optimizing timing of treatment minimizes irreversible disease progression

Dr Bryan McGill (Novartis Institutes for BioMedical Research, Chicago, USA) concluded by discussing the AAV-based gene therapies in development for a range of neurological diseases including familial Parkinson’s disease, X-linked myotubular myopathy, DMD and spinal muscular atrophy7,10. They can be successfully delivered to the CNS via the intraparenchymal, intracerebrospinal fluid or intravenous routes.

Early diagnosis for many of these diseases is important, as optimizing timing of treatment minimizes irreversible disease progression11. In DMD, early intervention to avoid tissue damage needs to be balanced with gene therapy being diluted due to muscle cells still dividing12.

AAV-based gene therapies in humans have demonstrated durable responses to single treatments

AAV-based gene therapies in humans have demonstrated durable responses to single treatments, with improvement in a range of clinical outcomes including motor and respiratory function13. In Parkinson’s disease the effects of a single dose targeting brain neurons has been shown to last over 10 years with transgene persistence in tissues14. Post-administration follow-up is important to monitor long-term outcomes and identify potential adverse events.


Educational financial support for this Industry Update satellite symposium was provided by Novartis Gene Therapies.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

  1. Petrich J, Marchese D, Jenkins C, Storey M, Blind J. Gene Replacement Therapy: A Primer for the Health-system Pharmacist. J Pharm Pract. 2020;33(6):846-55.
  2. Rosenberg SA, Aebersold P, Cornetta K, et al. Gene transfer into humans - immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med. 1990;323(9):570-8.
  3. American Society of Gene + Cell Therapy and Pharma Intelligence. Gene, Cell, & RNA Therapy Landscape. Q1 2021 Quarterly Data Report.
  4. Shahryari A, Jazi MS, Mohammadi S, et al. Development and Clinical Translation of Approved Gene Therapy Products for Genetic Disorders. Front Genet. 2019;10:868.
  5. Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet. 2003;4(5):346-58.
  6. Lisowski L, Tay SS, Alexander IA. Adeno-associated virus serotypes for gene therapeutics. Curr Opin Pharmacol. 2015;24:59-67.
  7. Piguet F, de Saint Denis T, Audouard E, et al. The Challenge of Gene Therapy for Neurological Diseases: Strategies and Tools to Achieve Efficient Delivery to the Central Nervous System. Hum Gene Ther. 2021;32(7-8):349-74.
  8. Mimuro J, Mizukami H, Shima M, et al. The prevalence of neutralizing antibodies against adeno-associated virus capsids is reduced in young Japanese individuals. J Med Virol. 2014;86(11):1990-7.
  9. Gil-Farina I, Fronza R, Kaeppel C, et al. Recombinant AAV Integration Is Not Associated With Hepatic Genotoxicity in Nonhuman Primates and Patients. Mol Ther. 2016;24(6):1100-05.
  10. Thomsen G, Burghes AHM, Hsieh C, et al. Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue. Nat Med. 2021;27(10):1701-11.
  11. Talbot K, E F Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017;24(9):529-33.
  12. Duan D. Dystrophin Gene Replacement and Gene Repair Therapy for Duchenne Muscular Dystrophy in 2016: An Interview. Hum Gene Ther Clin Dev. 2016;27(1):9-18.
  13. Mendell JR, Al-Zaidy SA, Lehman KJ, et al. Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy. JAMA Neurol. 2021;78(7):834-41.
  14. Chu Y, Bartus RT, Manfredsson FP, Olanow CW, Kordower JH. Long-term post-mortem studies following neurturin gene therapy in patients with advanced Parkinson's disease. Brain. 2020;143(3):960-75.
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