Currently, the D2R Initiative has identified four priority disease areas and associated strategic priorities:聽oncology, rare diseases,听infectious diseases,听and cardiovascular and cardiometabolic diseases. These priorities聽were developed by the Oncology, Rare Diseases, Infectious Diseases, and Cardiovascular and Cardiometabolic Diseases working groups, and will be used to guide strategic prioritization of funding opportunities including the Translational Impact Research program, Clinical Research and Development program, and other targeted programs of the D2R Initiative.

Oncology

D2R has identified Oncology as a prioritized area of strategic interest for the design, implementation and testing of novel genomic medicine-based personalized RNA therapeutic interventions. The research is expected to be multi-disciplinary and translational, supporting research programs likely to have a direct short-term or medium-term impact on treatment of patients with neoplastic or pre-neoplastic conditions. Below are criteria that will be used to evaluate and prioritize research proposals. These have been developed by the Oncology working group.

• Develop novel RNA-based advanced therapies for personalized treatment of cancers, including all aspects of development and implementation of personalized tumor neo-antigen vaccines in common cancers.
• Implement novel RNA-based technologies for cancer prevention. Specifically, target pre-neoplastic conditions and cells as seen in superficial bladder cancer, ductal carcinoma in situ (DCIS), pre-malignant colorectal polyps and others, in the general population or guided by population-specific, pre-disposing genetic variants, in indigenous and other vulnerable populations.
• Identification, characterization and validation of novel targets in tumor metastasis, including development of novel RNA modalities for pre-clinical testing and clinical research.
• Develop joint laboratory and clinical pipelines which implementation would characterize individual tumors in an iterative fashion over time, thereby informing the decision-making process to guide intervention at different stages of the disease. Pipeline to go from tumor acquisition, to pathology, to genomics, to transcriptomics, to immune profiling/IHC, to xenografts studies that together inform the tumor board for selection of the best patient-specific treatment options, to a therapy acquisition team, to the treating oncologist. Use the pipeline to bring novel treatment options in the form of 鈥渙ff label鈥� use, to 鈥渃ompassionate鈥� use of drug candidates under evaluation, novel RNA vaccines, novel CAR-T based interventions for rapid guided interventions. Such a program would focus on rare tumors initially (translocations, sarcomas, paediatric cancers) expressing rare variants and/or where treatment options are limited.
• Immunological enhancement of response to treatment, including interventions based on the microbiome. Develop biomarkers that could serve as surrogates of immune status and/or specific immune activation.
• Study the parameters responsible for non-responsiveness to tumor neo-antigens vaccines, including novel bioinformatic tools and AI to develop more personalized markers, as well as predictive tools for responsiveness (HLA etc.).

Rare Diseases

D2R has identified Rare Diseases as a prioritized area of strategic interest for the design, implementation and evaluation of novel genomic medicine-based RNA therapeutic options. The research is expected to be multi-disciplinary and translational, supporting research programs likely to have a direct short-term or medium-term impact on treatment of afflicted individuals. D2R will not prioritize specific rare diseases, but will consider all rare (incidence of less than 1 in 2,000) and ultra-rare (incidence of less than 1 in 50,000) diseases, that fall in the general categories that include but are not limited to neurological, developmental, metabolic, immunological, pulmonary and ophthalmological diseases, as well as rare tumors. D2R cannot support clinical trials per se, but can support any other aspects of research including target identification, target validation, pre-clinical studies, clinical research, if they are organized in a competitive translational framework. D2R will consider and support research programs where researchers and clinician scientists at McGill, McGill-affiliated hospital research institutes and partners can demonstrate a clear competitive advantage over current research done elsewhere for the selected disease area (D2R advantage). Below are criteria that will be used to evaluate and prioritize research proposals. These have been developed by the Rare Diseases working group.

• Access to patients and/or patient registries and other clinical resources where novel therapies can be tested.
• Demonstrated suitability of RNA therapies for the disease targeted, including strong rationale and preliminary evidence that RNA-based approaches hold promise (studies in preclinical models), and that RNA cargo can be delivered to the therapeutic site.
• Existing or high potential of partnership with the private sector to implement the proposed therapy with a time horizon of 3-5 years to translation to clinical trial(s).
• Previous preclinical and/or clinical expertise of assembled team in the disease.
• In-house access to cell or animal model systems for validation of proposed therapy with well-defined phenotypic markers and endpoints to assess efficacy, including patient-derived cell lines.
• Interdisciplinary activity among basic and applied researchers.
• Originality and competitiveness of the position of McGill/Quebec/Canada in the international research space relevant to the disease.
• Development of RNA-based therapeutics focused on diseases with higher prevalence in specific populations of Quebec and/or Canada, including indigenous communities.

Infectious Diseases

Infectious diseases continue to threaten many populations in Canada and globally, as illustrated in the recent COVID-19 pandemic. In addition, there are specific infectious disease threats that are emerging or predicted to emerge, and that could affect several vulnerable communities in Canada including indigenous people. RNA-based technologies have the potential to contribute to vigilance and precise diagnostics, but can also form the basis of novel treatments, and as seen in the COVID pandemic are an essential tool for large scale prevention through vaccination. 51吃瓜网has a long history of established strength in the study of infections caused by fungal, viral, bacterial and parasitic microbes, including the study of host factors that influence genetic vulnerability. D2R has selected Infectious Diseases as an area of strategic priority for certain of its programs. Priority will be given to research that will involve both laboratory researchers, and clinician scientists, as well as meaningful engagement of industry partners. Although any emerging infectious threat will be considered, chronic viral illnesses, bacterial infections and parasitology will be prioritized as affecting billions of people worldwide, and currently directly threatening the well-being of Canadians. Participation of international partners will be deemed important to tackle infectious diseases of global health relevance. The major areas of strategic interest have been identified by the Infectious Diseases Working Group as:

• Novel RNA-based or RNA-derived diagnostic tools for infectious microbes for monitoring and diagnosing specific threats.
• Novel RNA and nucleic acid-based intervention for the treatment of infectious diseases, including microbial and host derived host targets involved in all aspects of pathogenesis and host response; This can additionally include biofilms, inflammation, fibrosis and other pathological responses that exacerbate infections outcomes.
• Development of novel vaccines against validated targets in bacterial, viral, fungal and parasitic diseases.
• Implementation of genomic immunology approaches for the development and testing of new more efficacious and more 鈥減ersonalized鈥� vaccines, and in support of clinical testing.
• Development of vaccines against livestock and other reservoirs for zoonotic infections.

Cardiovascular and Cardiometabolic Diseases

D2R has identified Cardiovascular Disease (CVD) and Cardiometabolic Disease (CMD) as new prioritized areas of strategic interest, recognizing their position as leading causes of morbidity and mortality globally and the growing impact on younger populations. Despite the availability of effective therapies, uncontrolled hypertension, obesity and related CVD/CMD remain highly prevalent, underscoring the urgent need for novel diagnostic and therapeutic approaches. RNA-based technologies offer a transformative opportunity to address these unmet needs by uncovering new mechanisms of disease, identifying biomarkers, and developing innovative therapeutic targets.

51吃瓜网has a strong foundation in cardiovascular and metabolism research, with expertise spanning molecular biology, genomics, neurovascular sciences, vascular biology, pre-clinical models, and clinically phenotyped patient cohorts. Combined with D2R鈥檚 strengths in RNA science and technology, this positions the community to lead the development and translation of RNA-based strategies for CVD/CMD. Research is expected to be multidisciplinary and translational, aimed at programs with potential for near- or medium-term impact on patient care.

Below are criteria that will be used to evaluate and prioritize current CVD research proposals. These have been developed by the CVD working group:

• Demonstrated expertise in molecular medicine, novel RNA-based therapies, and internationally recognized research programs on mechanisms of CVD.
• Access to relevant patient cohorts, registries, and cardiovascular biobanks, as well as pre-clinical resources (organoids, hiPSC, animal models, patient-derived primary cells) for validation of RNA-based interventions.
• Access to a clinical research facility in which first-in-human, experimental medicine and phase 1 studies can be conducted and where deep cardiovascular phenotyping is possible (Centre for Innovative Medicine at RI-MUHC).
• Evidence from preclinical and clinical studies that the targeted CVDs are suitable for RNA-based approaches, addressing areas of unmet medical need where improved therapies are required.
• Interdisciplinary collaboration among basic, translational, and clinical investigators, with potential for partnerships with industry and demonstration of international competitiveness.

Based on these criteria, the following four diseases have been identified as strategic priorities for the current cycle of the TIR program:

1. Microvascular and small vessel disease (including microvascular disease of the heart, diabetic vasculopathy, and cerebral small vessel disease)
2. Hypertension
3. Cardiomyopathies (genetic and dilated)
4. Metabolic syndrome and diabetes

Future opportunities may expand to include additional diseases such as aortic stenosis, congenital heart disease, heart failure, arrhythmias, preeclampsia, and obesity. Consideration will also be given to areas such as sex differences in CVD, where 51吃瓜网has emerging strengths.