Periodic Reporting for period 1 - MMM (Medicine Made to Measure.)
Periodo di rendicontazione: 2023-10-01 al 2025-09-30
MMM is an intersectoral, innovative training network that receives funding from the European Commission (2023-2027) as part of the HE MSCA programme. It consists of nine beneficiaries, hosting 10 doctoral students, plus 14 associated partners providing training, PhD enrolment or secondment opportunities. MMM stands for “Medicine Made to Measure” and furthers all pathways in the pipeline towards single-patient treatment of nano-rare neurological diseases. Our network brings together international academic, industrial, governmental and patient organisation partners in a cross-specialty platform.
Although the last decade has seen a breakthrough in the field of personalised genetic medicine, currently 95% of rare neurological diseases (RNDs) still lack disease modifying treatment options. This is due to the rarity of individual RNDs, their sheer number, and the lack of appropriate translational and trial methodology for nano-rare diseases. Antisense-oligonucleotides (ASOs) are short, chemically modified, synthetic RNAs which, upon intrathecal delivery, distribute throughout the central nervous system (CNS), making them ideally suited for treating CNS diseases. ASOs offer particular promise for precision medicine due to their comparatively low production cost, a “programmable” sequence that can be flexibly targeted to almost any gene transcript target of choice, relatively low toxicity and flexible dosing regimens.
The ultimate goal of MMM is to establish the field of tailored ASO treatments for individuals with nano-rare RD mutations. We seek to develop core modules of a novel “out-of-the-box”, yet EMA-advised treatment development path for single patients with nano-rare mutations. At the same time these core modules offer a unique opportunity for doctoral candidates to be trained and involved in developing all aspects needed for tailored ASO treatment, eventually becoming the forerunners of developing tailored genetic treatments and streamlining tailored ASO treatment for RNDs in Europe, both in academia and industry.
Although the last decade has seen a breakthrough in the field of personalised genetic medicine, currently 95% of rare neurological diseases (RNDs) still lack disease modifying treatment options. This is due to the rarity of individual RNDs, their sheer number, and the lack of appropriate translational and trial methodology for nano-rare diseases. Antisense-oligonucleotides (ASOs) are short, chemically modified, synthetic RNAs which, upon intrathecal delivery, distribute throughout the central nervous system (CNS), making them ideally suited for treating CNS diseases. ASOs offer particular promise for precision medicine due to their comparatively low production cost, a “programmable” sequence that can be flexibly targeted to almost any gene transcript target of choice, relatively low toxicity and flexible dosing regimens.
The ultimate goal of MMM is to establish the field of tailored ASO treatments for individuals with nano-rare RD mutations. We seek to develop core modules of a novel “out-of-the-box”, yet EMA-advised treatment development path for single patients with nano-rare mutations. At the same time these core modules offer a unique opportunity for doctoral candidates to be trained and involved in developing all aspects needed for tailored ASO treatment, eventually becoming the forerunners of developing tailored genetic treatments and streamlining tailored ASO treatment for RNDs in Europe, both in academia and industry.
MMM started in October 2023. So far, MMM has completed its planned deliverables and milestones and is progressing well. Our main achievements in the first reporting period (October 2023 to September 2025) are the following:
WP1 Processes, Tools and Infrastructure:
- WP1.1 (University Hospital Heidelberg): The project aims at establishing a proof of concept for a targeted therapeutic strategy for ALS-KIF5A. Lead ASO candidates from two complementary approaches are now in evaluation. Furthermore, a large WGS/RNA Seq dataset was analyzed to identify cryptic splice variants and different approaches to prioritize SDLTs for targeted therapies were evaluated.
- WP1.2 (BianoGMP, Gera): A standardised, optimised manufacturing approach for splice switching ASOs has been established and currently needs to be scaled to clinically relevant amounts.
- WP1.3 (LMU, Munich): So far the relevant literature has been reviewed and the outline of the first paper has been defined (currently in the drafting/writing phase).
WP2 Preclinical Innovation:
- WP2.1 (Tübingen University): The project was able to prepare first proof-of-concept for a strategy of preclinical development of patient-customized splice-modulation ASO therapies targeting cryptic splice mutations, showcased by Ataxia telangiectasia (A-T; mutated gene: ATM). This strategy started from targeted patients’ individual cells lines, using only regulatorily approved ASO chemistry (nusinersen-analogous ASO-backbones), and gauged comparative effect sizes by multiple reference mutations/cell lines, and references both effect sizes and toxicity to multiple reference ASOs.
-WP2.2 (Leiden University Medical Center): After it turned out exon skipping was not a viable approach for WDR45, the DC performed a literal review to identify an alternative target. ANKRD17 was selected, and ASOs targeting exon 13 have been designed, produced by DC2 and exon 13 skipping has been confirmed in control cells for all designed ASOs. Future experiments will focus on skipping exon 13 in mutated cells (currently being generated in IPSCs) and test the safety of these ASOs in cell and animal models.
- WP2.3 (Biotalentum, Gödollö): A preclinical toxicity model utilising neural progenitor cells, microglia and THP-1 derived macrophages in the form of 2D cultures and cortical spheroids in 3D is under development.
- WP2.4 (Leiden University Medical Center): A literature review was done and data from in vivo toxicity studies received from collaborators in the USA were studied. Based on this an outline for in vivo toxicity studies for N=1 ASOs has been generated. Ethical approval to conduct this work has been applied for and received. Future work will involve testing known safe and toxic ASOs to assess the suitability of the study design.
WP3 Clinical Readiness:
- WP3.1 (mHealth, Bologna): A large set of candidate endpoints has been evaluated multi-modally under context-sensitive analysis in lab-based and real-life conditions for reliability and sensitivity to group-level longitudinal change, with scientific prerequisites for the prospective study as well as multi-endpoint n-of-1 models currently underway.
- WP3.2 (Cambridge University, UK): The current focus is on validating the candidate biomarkers in additional serum samples and writing up a manuscript for publication. Future plans include studies on neuronal models.
- WP3.3 (Uppsala University): While the way to the framework for single endpoint and multiple endpoints assessments has been paved, there are more aspects, inspired by the real practice, that need to be taken into account while framing the platform for multiple linked outcomes.
These research work packages are complemented by WPs for Individualised Training, Network-wide Training, Dissemination and Management. All doctoral candidates have a personal Career Development Plan and are enrolled in local PhD programmes. They also receive centrally organised training which is tailored to their needs and future career prospects.
WP1 Processes, Tools and Infrastructure:
- WP1.1 (University Hospital Heidelberg): The project aims at establishing a proof of concept for a targeted therapeutic strategy for ALS-KIF5A. Lead ASO candidates from two complementary approaches are now in evaluation. Furthermore, a large WGS/RNA Seq dataset was analyzed to identify cryptic splice variants and different approaches to prioritize SDLTs for targeted therapies were evaluated.
- WP1.2 (BianoGMP, Gera): A standardised, optimised manufacturing approach for splice switching ASOs has been established and currently needs to be scaled to clinically relevant amounts.
- WP1.3 (LMU, Munich): So far the relevant literature has been reviewed and the outline of the first paper has been defined (currently in the drafting/writing phase).
WP2 Preclinical Innovation:
- WP2.1 (Tübingen University): The project was able to prepare first proof-of-concept for a strategy of preclinical development of patient-customized splice-modulation ASO therapies targeting cryptic splice mutations, showcased by Ataxia telangiectasia (A-T; mutated gene: ATM). This strategy started from targeted patients’ individual cells lines, using only regulatorily approved ASO chemistry (nusinersen-analogous ASO-backbones), and gauged comparative effect sizes by multiple reference mutations/cell lines, and references both effect sizes and toxicity to multiple reference ASOs.
-WP2.2 (Leiden University Medical Center): After it turned out exon skipping was not a viable approach for WDR45, the DC performed a literal review to identify an alternative target. ANKRD17 was selected, and ASOs targeting exon 13 have been designed, produced by DC2 and exon 13 skipping has been confirmed in control cells for all designed ASOs. Future experiments will focus on skipping exon 13 in mutated cells (currently being generated in IPSCs) and test the safety of these ASOs in cell and animal models.
- WP2.3 (Biotalentum, Gödollö): A preclinical toxicity model utilising neural progenitor cells, microglia and THP-1 derived macrophages in the form of 2D cultures and cortical spheroids in 3D is under development.
- WP2.4 (Leiden University Medical Center): A literature review was done and data from in vivo toxicity studies received from collaborators in the USA were studied. Based on this an outline for in vivo toxicity studies for N=1 ASOs has been generated. Ethical approval to conduct this work has been applied for and received. Future work will involve testing known safe and toxic ASOs to assess the suitability of the study design.
WP3 Clinical Readiness:
- WP3.1 (mHealth, Bologna): A large set of candidate endpoints has been evaluated multi-modally under context-sensitive analysis in lab-based and real-life conditions for reliability and sensitivity to group-level longitudinal change, with scientific prerequisites for the prospective study as well as multi-endpoint n-of-1 models currently underway.
- WP3.2 (Cambridge University, UK): The current focus is on validating the candidate biomarkers in additional serum samples and writing up a manuscript for publication. Future plans include studies on neuronal models.
- WP3.3 (Uppsala University): While the way to the framework for single endpoint and multiple endpoints assessments has been paved, there are more aspects, inspired by the real practice, that need to be taken into account while framing the platform for multiple linked outcomes.
These research work packages are complemented by WPs for Individualised Training, Network-wide Training, Dissemination and Management. All doctoral candidates have a personal Career Development Plan and are enrolled in local PhD programmes. They also receive centrally organised training which is tailored to their needs and future career prospects.
We combine all approaches and methodologies in a sustainable pipeline for tailored ASO development within the funding period and beyond. MMM goes beyond even the latest genetic medicine approaches by pioneering and implementing a new paradigm of drug development: single patient tailored genetic treatments - hyper-individualised, but at the same time streamlined and rapidly scalable in all of its core development modules, preparing availability to nano-rare RND patients across Europe.
The progress of the projects has been presented at multiple (inter-)national conferences and has so far resulted in 5 peer-revied papers. MMM’s website (https://medicine-made-to-measure.eu/(si apre in una nuova finestra)) provides an overview of our goals, news and individual research activities, as does our LinkedIn profile (https://www.linkedin.com/company/mmm-medicine-made-to-measure/(si apre in una nuova finestra)). All fellows perform outreach activities to share their research with the general public.
The progress of the projects has been presented at multiple (inter-)national conferences and has so far resulted in 5 peer-revied papers. MMM’s website (https://medicine-made-to-measure.eu/(si apre in una nuova finestra)) provides an overview of our goals, news and individual research activities, as does our LinkedIn profile (https://www.linkedin.com/company/mmm-medicine-made-to-measure/(si apre in una nuova finestra)). All fellows perform outreach activities to share their research with the general public.