Gene therapy for the HSPs

What’s the current status?

This article is in two parts – the first is a perspective on the suitability of the current drug development process with respect to the development of gene therapies. The second part addresses technical limitations holding back progress in the development of gene therapies.

The head of the US Food and Drug Administration’s (FDA) biologics center says the current drug development process is not well-suited for gene therapy products.

He says there needs to be a total rethinking from clinical trial designs, statistical tools, manufacturing practices to global regulatory harmonization to get new gene therapies to patients more effectively.

Peter Marks FDA

Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), says there needs to be a paradigm shift to help get new gene therapies to market in an article published in Expert Opinion on Biological Therapy on 3 April. While noting there have been some successes, he questions why more patients haven’t been able to reap the benefits of gene therapies.

“Although there is obviously no single correct answer to this question, one can start by considering whether the current framework for the clinical development of small molecule drugs frequently being followed for the development of gene therapies is the wholly appropriate paradigm to be following,” Marks wrote. “Certainly, there are aspects of the paradigm that are quite applicable, such as understanding the non-clinical aspects of the product in development, the use of good manufacturing practices for production, and the demonstration of safety and effectiveness for the intended use. However, there are other aspects of gene therapies that may lend themselves to the application of other paradigms.”

Specifically, Marks says current gene therapies use a vector backbone, usually an adeno-associated virus (AAV) or a lentivirus, to deliver the transgene. He says new gene therapies could reuse information related to the vector backbone to speed their development.

Part of proving to regulators a product is effective is showing that its endpoints are statistically significant which can be extremely difficult especially when they are meant to treat rare diseases in small patient populations.

Marks suggests one area to look at to overcome that challenge in gene therapies is to use biomarkers in non-clinical models where there is a correlation with therapeutic response. He also suggests use of Bayesian clinical trial designs, which allow researchers to calibrate the trial based on ongoing data gathering, can be another useful means of dealing with extrapolating data from small patient populations.

Read the full article 

SOURCE: Regulatory Affairs Professionals Society: Regulatory Focus™ > News Articles > 2022 > 4 © 2022 Regulatory Affairs Professionals Society.

Marks calls for new gene therapy development paradigm

Posted 05 April 2022 | By Ferdous Al-Faruque 

There are two fundamental challenges preventing faster progress and more widespread application of gene therapies in treating genetic diseases. These challenges could be described as a ‘packaging’ challenge and a ‘delivery’ challenge.

The main form of ‘packaging’ currently available for gene therapy is a very small ‘container’ into which only smaller genes can fit. Genes come in varying sizes, including the 80 or so HSP genes. Some can fit in the container and some can’t.

The ‘delivery’ challenge is how to safely and effectively deliver the gene therapy to where it needs to be. For neurological diseases such as the HSPs, this means delivery to a particular location in the brain, which is surrounded by what is known as the blood-brain barrier, and quite some barrier it is.

This review explores ideas and emerging technologies for addressing these challenges and limitations to having effective gene therapies available.

Mimoun Azzouz

Introduction: Gene therapy provides the exciting opportunity of a curative single treatment for devastating diseases, eradicating the need for chronic medication. Adeno-associated viruses (AAVs) are among the most attractive vector carriers for gene replacement in vivo. Yet, despite the success of recent AAV-based clinical trials, the clinical use of these vectors has been limited. For instance, the AAV packaging capacity is restricted to ~4.7 kb, making it a substantial challenge to deliver large gene products.

Areas covered: In this review, we explore established and emerging strategies that circumvent the packaging limit of AAVs to make them effective vehicles for gene replacement therapy of monogenic disorders, with a particular focus on diseases affecting the nervous system. We report historical references, design remarks, as well as strengths and weaknesses of these approaches. We additionally discuss examples of neurological disorders for which such strategies have been attempted.

Expert opinion: The field of AAV-gene therapy has experienced enormous advancements in the last decade. However, there is still ample space for improvement aimed at overcoming existing challenges that are slowing down the progressive trajectory of this field.

SOURCE:  Expert Opin Biol Ther. 2022 Jan 6;1-14. doi: 10.1080/14712598.2022.2012148. Online ahead of print.  PMID: 34904932

Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders

Lara Marrone  1 Paolo M Marchi  1 Mimoun Azzouz  1

Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.


  1. Is there a better drug than Baclofen for HSP or anything for severe spasticity & muscle weakness.

    1. Editor’s Note: Yes there are alternative drugs to Baclofen for treating and managing spasticity. There is also intrathecal Baclofen where the drug is delivered to a precise location, often resulting in much higher effectiveness than is possible with oral dosing. Regarding muscle weakness, one of the big challenges in treating the HSPs is the coexistence of both spasticity and weakness in the muscles in varying degrees in different people with HSP. Drugs to treat spasticity can also make weak muscles weaker, and compound mobility problems. Getting the balance right between treating spasticity and avoiding further muscle weakness is a fine line in managing HSP. Talk to your neurologist if your current treatment is inadequate.

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