Competition Objectives: 

Part the Cloud, a program through the Alzheimer's Association, announces a targeted challenge funding program focused on increasing early phase human trials (Phase 1 and Phase 2) of potential therapies tailored to the genetic underpinnings of Alzheimer’s disease and related dementias internationally. 

Background: 

A number of factors and processes likely contribute to the development of brain diseases such as Alzheimer's disease, and these may not be the same for every individual. More than 100 genes have been associated with the development of Alzheimer’s as either risk or protective factors, each one influencing biological changes in the brain. Because of this variation in disease processes between individuals, there is a significant opportunity for personalized gene editing and therapy in Alzheimer’s. Evidence from the trials that led to the recent approvals for two new therapies targeting the abnormal accumulation of beta-amyloid “plaques” suggest potential subpopulations of responders and non-responders. The complex interplay of factors and processes leading to the development of neurodegenerative disease points towards combination therapy of two or more drugs — with behavioral interventions that target distinct biological processes as the likely future of treatment for Alzheimer’s and the other brain diseases that cause dementia. Personalized medical approaches to address an individual’s biological circumstances is the future of treatment for Alzheimer’s throughout the disease continuum.

Gene targeting therapies have existed for some time, but only recently have they become viable for clinical use. The COVID-19 vaccines utilized novel mRNA technology. Other new technologies such as small interfering RNA (siRNA), antisense oligonucleotides (ASOs), and CRISPR are being evaluated in the clinic for a range of diseases like sickle-cell anemia and heart disease. In early 2023, the U.S. Food and Drug Administration (FDA) approved ASO approaches for treatment of amyotrophic lateral sclerosis (ALS) and in late 2023, the FDA approved a CRISPR based therapy for sickle cell anemia, moving these approaches to care in real time. These recent approvals demonstrate the timeliness of leveraging approaches that build on the technological advances of ASOs, siRNA and CRISPR, as well as other approaches for gene modifications for Alzheimer’s and other brain diseases that cause dementia. The Alzheimer’s Association and Part the Cloud are already leading the way in these therapeutic approaches for Alzheimer’s disease and other related dementias. Previous Part the Cloud awards include an ASO therapy targeting tau, a gene therapy targeting brain derived neurotrophic factor (BDNF), and an adult stem cell therapy. The BDNF gene therapy trial has shown that a single injection can lead to prolonged increases in brain BDNF levels. While these advances are pushing the field forward, a greater emphasis on these approaches, or combinations of these approaches with other therapies, could lead to unprecedented acceleration in the treatment of Alzheimer’s.
Slowing or preventing Alzheimer’s disease is a major public health need, and it is essential that the field begin to examine these promising new approaches. While many academic investigators and companies have successfully discovered candidate therapeutics, and have succeeded in the non-clinical stages of development, funding for the next phase to transition into human testing can be a major stumbling block. Most government and non- government grant mechanisms support preclinical development or mid to later clinical trials testing drug efficacy in humans, but there are few mechanisms for supporting the critical earlier Phase I trials in humans or have restrictions on funding that limit the forward momentum for therapeutic approaches. 

Potential themes: This new grant mechanism aims to fill the gap in Alzheimer’s disease and related dementia clinical trials for advancing potential gene targeting therapeutics forward by providing support for early phase studies (Phase 1 and Phase 2).

Funding and award period: 

Each grant is limited to $1,000,000 (direct and indirect costs) for Phase 1 studies and $2,000,000 for Phase 2 studies over two or three years. We anticipate funding a mix of phase 1 and phase 2 studies with available funding, minimum of 10 clinical trials. Indirect costs are only allowed for not-for-profit institutions, and are capped at 10 percent (rent for laboratory/office space is expected to be covered by indirect costs paid to the institution). No indirect costs are allowed for profit organizations. 

Letter of Intent (LOI) Review Procedures: All LOIs will be evaluated prior to invitation to submit a full application. Only LOIs that meet program specific guidelines as outlined in this request for applications will be invited to submit full applications.

Deadlines and award dates: Letters of Intent (LOI) must be received by 5:00pm EST, October 24, 2024. Letters of Intent will not be accepted after this date. No exceptions will be made. All LOIs must be completed and submitted online through our interactive system Proposal Central at http://proposalcentral.com. (No paper copies or emailed versions will be accepted)

The on-line LOI is approved and invited to submit a full proposal, an email notification will be sent from Proposal Central granting access to the on-line application. The online system must be used to submit a grant application—hard copies of the application will not be accepted. 

Each LOI is evaluated with attention to: 

● Demonstrable innovation/novelty of the proposed project (especially in the context of the PIs recently funded work)

● Alignment with the research priorities of the PTC request for applications and the Alzheimer’s Association, including population, proposed therapeutic, outcome measure(s) and overall scientific rationale 

● Evidence of methodological rigor of the trial, including patient selection, target engagement, outcome measures, etc. being proposed

For those invited to submit, Full applications must be received by 5:00pm EST, January 9, 2025. 

The full grant application consists of the following: 

1. Problem Statement – 1 page 

2. Work Plan – 5 pages; Efficacy should not be the primary outcome for studies at phase 1 and phase 2; however, it may be an exploratory outcome. All applications should have clear Go/No Go criteria to the next phase of clinical development of the therapy, which should be clearly outlined in the application. The application must demonstrate how data from the proposed study will inform future trials. 

3. Available Resources & Budget Justification – 2 pages; If awarded, a full budget of planned expenses will be required. 

4. Data Management and Sharing Plan – 3 pages; we recommend using the provided amended NIH template. When data sharing may be limited, applicants must explain such limitations at the time of application. 

5. Recruitment Plan - 1 page; the Association expects all trials to match or exceed the diversity of their local population at a minimum. Award must maintain at least 20% minimum representation of minoritized participants. The Association will withhold payments if recruiting does not achieve this level of diversity. 

6. Milestones – 3 pages max 

7. Reference and Citations – 1 page 

8. Response to review comments – For resubmissions only – 1 page 

9. Therapeutic Rationale – 1 page 

10.Gantt Chart – 1 page (Optional) 

11. Biosketch (PI/Co-PI/Key Personnel) – 5 pages max for each 

12. Research Project Leadership Plan – 5 pages max

Applications will be reviewed with special attention to: 

● Significance of the question being studied & rationale of the target being pursued 

● Applicant information 

● Quality of the proposed trial design 

● Quality and adequacy of available resources and budget 

● Impact-Risk 

Scientific and technical review will be conducted from January - March, 2025. The second- level review by the Alzheimer’s Association and subject matter experts in September 2024 and funding is anticipated to be awarded by April 30, 2025. 

Reporting requirements: Awardees will be required to provide sixth month milestones, and have bi-annual discussions with the Alzheimer’s Association. Annual scientific progress and financial reports are required. Continuation of the grant over the awarded duration is contingent upon meeting the scientific milestones, achieving a minimum participant recruitment of 20% minimum representation from minoritized participants, and upon timely receipt of scientific and financial reports. Representation of study participants should be reflective of the communities that are being engaged for this study. 

Budget: A budget summary for the proposed research project is required and must be submitted with the application and within the allowable page limits. However, if the application is to be awarded, a more detailed budget will be required and must be approved before the disbursement of funds. Your budget must not exceed the maximum amount of the award, $1,000,000 (inclusive of direct and indirect) over two or three years. 

Allowable Costs include: 

● purchase and care of laboratory animals; 

● small pieces of laboratory or clinical research equipment; 

● special use computer hardware and software for neuropsychological or imaging studies; 

● laboratory or clinical supplies; 

● salary for the Principal Investigator; 

● salary for scientific staff (including post-doctoral fellows and graduate students) and technical staff (including laboratory technicians and modest secretarial support); 

● open access publication fees for journal articles related to the funded research project; 

● participant remuneration adhering to the NACC ADRC Best Practices located here: https://naccdata.org/adrc-resources/best-practices

 ● membership to ISTAART, the professional society of the Alzheimer’s Association and other scientific associations 

● professional development and communication training; and 

● support for travel to scientific and professional meetings and additional support for travel expenses necessary to carry out research planned– this may include site visits. A total of $12,500 over a three year period may be requested for travel purposes and is not to exceed $7,000 in any given year. 

● costs associated with the management and sharing of research data are allowable.

Costs not allowed under this award include: 

● Computer hardware or software for investigators (e.g. Microsoft Office, mouse, monitor, computer parts) 

● Laboratory equipment such as freezers, ultracentrifuges, RT-PCR, Microscopy/imaging equipment 

● Service contract fees for equipment 

● Construction or renovation costs 

● Tuition 

● Rent for laboratory/office spaces 

● Visa costs and fees 

● Expenses such as Data Network Recharges and Computing and communication devices support services 

● General liability insurances, such as GAEL 

● Wire and currency exchange fees 

● Salary and/or compensation for Alzheimer’s Association Staff or current members of the Alzheimer’s Association Medical and Scientific Advisory Group (MSAG) and the International Research Grant Program (IRGP) Council. A complete list of MSAG and IRGP Council members can be found on our website alz.org/grants. 

For more information: Contact grantsapp@alz.org