• Use of pluripotent stem cells for the discovery of new therapeutic targets for Huntington's disease. Interview with Graziano Martello and Anna Maria Gambetta, University of Padua

Use of pluripotent stem cells for the discovery of new therapeutic targets for Huntington's disease. Interview with Graziano Martello and Anna Maria Gambetta, University of Padua

May 2, 2024

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The patent ‘New therapy for Huntington's disease’ is the most viewed patent on the KS platform in March. To fully understand the innovation behind this technology, we had the pleasure of interviewing Graziano Martello, Full Professor of Molecular Biology at the University of Padua, and Dr Anna Maria Gambetta, Research Associate at the same university.

The technology is based on the use of genes capable of counteracting the toxic effect of mutant proteins involved in the pathogenesis of certain neurodegenerative diseases, such as Huntington's disease. By screening the genome of stem cells, genes capable of neutralising this toxicity have been identified, paving the way for innovative gene therapy.

Conventional gene therapies focus on the delivery of missing or defective genes. In the case of Huntington's disease, we have a protein that acquires toxic functions, and our approach is to counteract this toxicity.

This is therefore a therapeutic strategy that offers new perspectives for the treatment of neurodegenerative diseases, overcoming the challenges related to the specificity and efficacy of current therapies.

The research team is already evaluating further applications of the technology, expanding its scope to treat a broader range of polyglutamine-related diseases. With the support of the NRRP and the growing interest in biotechnology, this new therapy could soon become a clinical reality for thousands of patients worldwide.

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Tell us about your background and role/interests in the world of research? 

Prof. Graziano Martello: I am a lecturer at the University of Padua. I came back 10 years ago from the University of Cambridge where I did a PhD on pluripotent stem cells, which is what my lab is still involved in now. We do basic research, studying the biology of these cells, but we also have a translational research strand where we use these cells to study more impactful technologies for neurodegenerative diseases.

One example of the application of pluripotent stem cells is the generation of hiPSCs (human induced Pluripotent Stem Cells) from patients and then differentiating them into the target cell type of the disease.

Dr. Anna Maria Gambetta: After graduating in Food Biotechnology, I continued my studies by undertaking a PhD in Molecular Medicine. During this course, I focused on the project in question, devoting myself to the validation of the genes identified during screening. This educational experience allowed me to appreciate first-hand the potential of this approach, especially in models that are increasingly complex and close to the human context. This further fuelled my interest and determination to contribute to the realisation of a therapeutic product that can offer hope and dignity to people affected by the disease.

Motivated by this vision, together with Prof. Graziano Martello and the support of our team, we founded DNAswitch, a start-up dedicated to the development of gene therapy treatments for Huntington's disease patients and therefore based on this patent.

Can you briefly introduce us to what the technology consists of. How it works and how it improves on the 'status quo' of technologies currently used in the field of gene therapy with viral vectors or mRNA. 

Click here to enter text.Huntington's disease is caused by a toxic protein and what we did was to identify genes whose activation could neutralise this toxicity. The identification of these targets was done using stem cells as a screening platform, selecting genes whose expression could preserve the survival of cells carrying the pathological mutation. The genes that exerted the protective function were carried in the form of mRNA or within adeno-associated viral vectors in model organisms, achieving very encouraging curative results. Our gene therapy and thus our 'armaco' is based on this principle.

The patent covers the delivery of these genes via different modalities, such as viral vectors or messenger RNA.

There are other therapeutic approaches for this disease and there are ongoing clinical trials. Since Huntington's disease is due to a gene mutation that produces the toxic protein, attempts are being made to block the production of that protein. However, such approaches are complicated by the fact that the mutant huntingtina protein is very similar to its healthy counterpart. So, both are affected, but the healthy huntingtin is essential for the cell's functionality.​​ ​​ ​

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The research project for a new therapy for Huntington's disease: from idea to market potential.

Huntington's disease is a rare condition, but among them it is one of the most widespread, with a prevalence of one in every 10,000 people. In Europe and North America alone, it is estimated that at least 80,000 people are affected and more than 150,000 people at risk are still undiagnosed. To date, Huntington's disease is an incurable disease, so the commercial landscape is devoid of competition.

There are already some gene therapies on the market. The market is represented by health insurances or health systems that 'reimburse' these drugs. The cost for these therapies ranges from 1 to over 3 million euros per patient. For example, a gene therapy, similar in incidence - which is SMA - treats about a thousand patients a year, generating a revenue of more than $1.5 billion per year. This drug is marketed by Novartis and was approved in 2020.

These numbers may seem exorbitant, and they are, but one must consider the fact that the course of a degenerative disease can take up to several decades and the accumulated direct and indirect medical costs can exceed 1.5 million euros.

Suffice it to say that between the ages of 30 and 40, one begins to lose control of motor skills, which is followed by the manifestation of psychiatric symptoms. Patients become non-self-sufficient and have to be cared for and looked after completely, perhaps for the next 20 years. Thus, the monetary and social cost is probably even higher than for 'gene therapy'. And that is why even existing ones are currently reimbursed.

Also contributing to the final price of these treatments are the very high development costs and the small patient pool on which they have to be amortised. Since these are rare diseases, in order to cope with this gap between costs and number of patients, pharmaceutical companies that invest in the development of these therapies receive subsidies and incentives through 'orphan drug designation'. This is a pathway that allows - being the only therapy for that disease - to shorten the time and cost of regulatory pre-clinical and clinical trial, making drug development particularly attractive to investors.

Then clearly we hope to bring these costs down, but at the moment this is the market we have to refer to.  ​​​ ​​​

​​Have you set up a spin-off to exploit this patent? What research and development activities do you intend to carry out? 

We set up a start-up just a few weeks ago. It is called DNAswitch and its mission is to utilise this patent, bridging the gap between research results and the clinical application of them.

To date, we have demonstrated the research grade efficacy of our therapeutic approach by successfully testing it on two animal models of the disease, and on neural progenitors derived from induced human pluripotent stem cells derived from Huntington's disease patients.

The research and development activities that the spin-off intends to carry out are aimed at optimising the delivery of the therapeutic product, validating potency, and identifying biomarkers on patient-derived mature striatal neurons.

The next step in the development of this technology involves pharmacokinetic and pharmacodynamic testing in a Good Laboratory Practice (GLP) compliant environment, using a clinical-grade (GMP) drug formulation. These tests will be conducted at certified institutions, such as Clinical Research Organisations (CROs). At the same time, we will enter into dialogue with health authorities, such as the Italian Medicines Agency (AIFA) and the European Medicines Agency (EMA), to initiate the regulatory pre-clinical phase and obtain approval.

These research and development activities require large resources (e.g. private funding and venture capital), to access which DNAswitch needs to have its own identity in order to establish itself as an economic interface.

As a reality, we are in the process of being recognised as a University Spin-Off of the University of Padua. NRPP and biotech: How has the NRRP been active in the field of new drugs and therapies? I am referring to investments, projects and initiatives.  

In our case, the NRRP – National Recovery and Resilience Plan is proving to be very effective. A significant part of the NRRP is dedicated to the development of RNA-based drugs. We got funding because one of the methods to deliver therapeutic genes is through viral vectors or using RNA. Therefore, we are also testing that method of delivery through the NRRP.

However, it is important to emphasise that this application is always covered by the patent: therapeutic genes administered with viral vectors, RNA or other methods.

Graziano, have you noticed any differences between the national and international landscape with regard to research and investment in this area?  

Yes, there are significant differences between the national and international landscape regarding research and investment in gene therapies for neurodegenerative diseases. At the international level, especially in countries with a strong scientific and technological tradition such as the United States, the United Kingdom and some Western European countries, there is more investment and greater availability of financial resources. These countries often have high-level research institutes, universities, hospitals and large biotech companies that focus specifically on developing innovative therapies for neurodegenerative diseases. In Italy, despite some progress such as the funds allocated by the PNRR, investment and research in gene therapies may be limited compared to other countries. However, even in the US, despite high investments, the failure rate of biotech start-ups is high. This highlights the challenges and risks associated with developing innovative therapies, despite the financial resources available.

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New therapy for Huntington's disease

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