Compassionate Care ALS (CCALS), a nonprofit located in Falmouth, Massachusetts, currently works with more than 1,050 ALS families in 47 states and multiple foreign countries.  Funding from ALSFAC WE CARE will allow CCALS to grow its staff to serve more ALS patients their families, communities, and healthcare providers.  We will provide resources including equipment, educational opportunities, Medicare/Medicaid assistance, communication assistance, guidance and awareness with regards to living with ALS, caregiving, and exploring end-of-life when invited, all at no cost to families across the United States.

As a patient-driven, primarily volunteer organization, the mission of ALS Ride For Life is to serve the ALS community by assisting patients and their families through a variety of supportive services to ease the financial and emotional stress this disease places on families, raising research funds to find a cure, raising public awareness, and providing the community with the latest ALS news, information, and inspiration. With a minimal staff (the equivalent of 2 employees), an active board of directors, and a team of volunteers.

To apply for our Mobility Matters Program or one of our other grants, follow this link: https://alsrideforlife.org/programs-assistance/

Overview:

Organoids are a powerful new and compelling technology for studying disease biology. Several different and complementary organoid models currently exist with relevance to ALS, but none of these models has been tested across multiple ALS iPSC lines, and all have been created using different lines/genetic backgrounds making comparisons between/among them challenging.

The reagents and assays used to assess ALS phenotypes have likewise varied. This variability and limited scale make it challenging to interpret results and to establish methodologic robustness.

This targeted RFP aims to answer the question: are there reproducible ALS phenotypes (pathology, omics, biomarkers) that are detectable within and/or across organoid models created from human C9orf72 and TDP43 mutation-carrying lines that differ from organoids derived from healthy gender and age-matched controls.

We are specifically looking for reliable ALS-relevant phenotypes that are widely observed (regardless of which line was used), reproducible, easily measured, and appear as early as possible, so as to potentially enable humanized disease modeling and utility for future therapeutic development.

We are ideally looking for assembloid models incorporating corticospinal motor neurons, spinal motor neurons, and muscle cells, so as to form a true ALS “circuit”, but will also consider applications utilizing any two out of these three cell types/regions. In addition to the “required” cell types, groups are also encouraged to incorporate multiple additional cell types, including glial cells, into their organoid models so as to more faithfully recapitulate the full extent of disease biology.

At the end of the grant period, we plan to invite all the funded labs back together for a follow- up workshop to compare methodologies, share data, discuss technical challenges, and brainstorm ideas for next steps. We encourage collaborative proposals and are hoping to fund a

diverse range of models/methods so as to accelerate the field. Experience developing organoids and compelling preliminary data will be important criteria for the review committee.

Materials Provided:

We will provide funding for proposals to develop organoids from 5 male C9ORF72 ALS and 5 age-matched control iPSC lines from the Answer ALS cohort, 1 C9orf72 ALS and 1 matching revertant control line, and 1 M337V line and 1 matching wild type/revertant control line from the INDI cohort, all at similar passage numbers. This will allow everyone to compare the phenotypes in their models based on identical lines. All lines will be provided to groups in a blinded fashion to better enable validation of independent approaches.

Where possible, funded labs will also be provided with standardized antibodies for the following:

• p-TDP43
• C and N-terminal TDP43
• DPR analysis will be performed at Mayo Clinic using the antibodies developed by Dr. Len Petrucelli’s group

Outcome Measures:

There are two key measures of success we would like the funded labs to address: maturational state and demonstration of ALS-relevant pathophysiology.

Cellular Maturation (proof of basic biology):

• Transcriptomic signatures (groups are encouraged to perform both snSEQ and bulk RNA transcriptomic analyses if possible)
• Please provide information as to the maturation state of the cells in your organoid models via at least 1 of the following immunohistochemical markers:
  1. ChAT expression
  2. UCHL1 expression
  3. GFAP expression
  4. Markers of NMJ maturation/innervation (for those organoid models that include muscle)
• Please provide information as to the maturation state of the cells in your organoid models via at least 1 of the following functional assessments:
  1. Electrophysiologic measures of cellular activity

1. Calcium imaging of cellular activity
2. Ability to drive muscle fiber contraction via stimulation of connecting neurons (for those organoid models including muscle)
3. Measures of synaptic density
4. Other functional assessments

Recapitulation of ALS phenotypes (necessary for translation):

1. Validation of DPR production in the C9 When do DPR’s appear? Which DPR’s?
2. Accumulation of RNA foci in the C9 Which cell types do you see foci in? What % of cells show foci? How many foci on average are there per cell? What is the earliest timepoint for reliable detection of foci?
3. Are you able to detect translocation of TDP43 out of the nucleus of corticospinal motor neurons and/or spinal motor neurons in your organoid models? If so, what is the earliest timepoint for reliable detection?
4. Are you able to detect other signs of TDP43 dysfunction in your models (changes in transcriptomics, presence of cryptic exon inclusion/splicing defects, etc)? If so, what is the earliest timepoint for reliable detection?
5. In those C9 and TDP43 derived organoids which include muscle, are you able to detect changes in NMJ’s? (numbers, size, innervation status, electrophysiological responses, etc) If so, what is the earliest timepoint for reliable detection?
6. Are you able to detect other signs of neuropathology in your organoid models? (e.g. cell death, inflammation, synapse loss, axonal changes, etc) If so, what is the earliest timepoint for reliable detection? We suggest using both an NFL assay and an LDH release assay to measure differences between ALS and control

Funding Timelines:

Applications open: November 20th, 2023 Applications due: January 31st, 2024 Anticipated earliest start date: June, 2024 Submit to: https://app.box.com

Grants are for the support of 2-year proposals of up to $300,000 USD total (inclusive of a maximum of 15% in indirect costs). Costs for lines and antibodies will be contracted separately by ALS Finding a Cure (and do not need to be included in the requested budget). Support will not normally exceed 2 years and applicants should submit proposals that are compatible with a 2-year time frame. The continuation of funding within this period will be subject to the submission of satisfactory progress reports, which will be required at six-month intervals.

Application Process

1. Please provide a cover letter addressed to ALS Finding a Cure and the Leandro Rizzuto Foundation including:
   1. Proposal Title
   2. Total costs (15% overhead cap)
   3. Number of milestones and related costs (to equal amount above)
   4. List of all investigators and institutions (and letters of collaboration if external to the PI’s lab and institution)
   5. Name and contact information for person(s) responsible for contracts
   6. Address for mailing of payments
2. Provide a study plan including:

• A brief abstract suitable for media release to the lay public if the application is successful
• Project Plan, Background, and Timeline (max. 5 pages) including:
  • Study background and rationale/significance
  • Study objectives/specific aims (i.e. how you plan to address the success measures outlined above in the RFP)
  • Supporting/preliminary data;
  • Experimental design/research plan;
• Detailed itemized budget and budget justification
• Description of study milestones, including the costs associated and timeline of specific deliverables
• Any research funding from other funding sources that relates to the proposed work

3. Signed and dated investigator CVs
4. Financial Disclosure Form: use either NIH form https://ethics.od.nih.gov/forms450, or an equivalent institutional form.

Organizations Commit $2M towards New International ALS Diagnostics Effort

 Boston, MA., Washington, D.C., and Palm Beach, FL (August 16, 2023) — ALS Finding a Cure^® (ALSFAC) and The ALS Association have awarded seven new grants worth a total of $2 million to support the development of early diagnostics for ALS.

More than 150 years after the disease was first defined, there are currently no universally accepted diagnostic approaches for ALS. In order to receive an ALS diagnosis, patients must first undergo a battery of tests designed to rule out other conditions. This is highly problematic because it can take a year – or sometimes even longer – for a person with ALS to receive the correct diagnosis. While these individuals are searching for a name for their affliction, they are frequently bounced to multiple doctors, can receive unnecessary (and expensive) surgical procedures and medications, and can become ineligible for ALS clinical trials.

To address this challenge, ALSFAC launched the Early ALS Diagnostics Initiative to identify promising molecular, digital, imaging, and electrophysiological diagnostic approaches for ALS. After receiving a Partnership Grant from The ALS Association, ALSFAC was able to increase the number of projects supported by the initiative and expand its reach internationally..

“Now is a time of unprecedented promise for the field of ALS research and drug development,” said Merit Cudkowicz, M.D., chief medical officer of ALS Finding a Cure^®. “This collaboration between foundations has made possible the support needed to shorten the time to diagnosis. This has been a long-time interest for ALSFAC, and we look forward to advancing a solution towards this key need for the field.” Cudkowicz also serves as chief of neurology at Mass General Hospital and the Julieanne Dorn Professor of Neurology at Harvard Medical School.

Kuldip Dave, Ph.D., senior vice president of research at The ALS Association, reinforced the importance of this collaborative initiative.

“The longer it takes for someone to be diagnosed, the longer they are waiting to access the multidisciplinary care, treatments and trials that may help them live longer or with a better quality of life,” Dave said. “That’s why this partnership with ALS Finding a Cure to support the development of new diagnostic approaches is so important. By combining our dollars, we can have a larger impact – funding more projects from researchers all around the world.”

The seven awardees are:

Erez Eitan, Ph.D., NeuroDex – The goal of this project is to develop a blood test that could be used to diagnose ALS early in the disease process by measuring levels of specific messenger RNAs regulated by TDP-43. TDP-43 is a protein normally located in the nucleus of cells in the brain and spinal cord that helps control the proteins produced from a number of different genes. However, in approximately 97% of people with ALS, clumps of misfolded TDP-43 are found in the cytoplasm of motor neurons, affecting normal mRNA production.

Mark Garret, M.D., Massachusetts General Hospital / Harvard Medical School – The investigators are aiming to develop a decentralized and open innovation platform to remotely monitor individuals at higher risk of developing ALS. Assessment measures will include limb activity, speech and cognition/behavior.

Roisin McMackin​, Ph.D., Trinity College Dublin, Ireland – The research team will measure nervous system function of individuals with C9orf72 mutations but no ALS symptoms using electroencephalography (EEG) and transcranial magnetic stimulation (TMS) to identify which functional changes can help predict disease development. C9orf72 mutations are the most common genetic cause of ALS.

Patrick Oeckl​, Ph.D., Ulm University Hospital​, Germany – The aim of this project is to study cerebrospinal fluid (CSF) samples taken from people with ALS-linked genetic mutations but no symptoms to identify small protein fragments called peptides that are associated with the early stages of ALS development. These results could then be used to develop a diagnostic test.

Ghazaleh Sadri-Vakili​, Ph.D., Massachusetts General Hospital / Harvard Medical School – The researchers are focused on identifying “breakpoint gene fusions” associated with ALS in blood and CSF samples to serve as early biomarkers of the disease. These events, which link two previously independent genes, are frequent in cancers and have been used as biomarkers in oncology to stratify disease and to improve treatment through precision medicine.

Ian Thrippleton​, Ph.D., NemDx – Through this project, the researchers are aiming to develop a comprehensive blood test for ALS that will measure TDP-43 activity along with several other biomarkers associated with both sporadic and familial ALS. They will then use this test to determine whether this combination of biomarkers can help divide people with ALS into subgroups.

Philip C. Wong​, Ph.D. Johns Hopkins University – The research team will lay the foundation for a diagnostic test by measuring CSF levels of an abnormal protein that is produced when TDP-43 is lost from the nucleus of neurons and stops working normally. They will then determine whether the assay is sensitive enough to detect this abnormal protein in blood samples.

About ALS

ALS is a progressive neuromuscular disease that destroys muscle-controlling nerve cells called motor neurons. As these cells deteriorate and are eventually lost, the muscles they control become weak and then nonfunctional. Each person’s disease course is unique, but eventually most patients will not be able to stand or walk, get in or out of bed on their own, use their hands and arms, or breathe without assistance. Currently, there is no cure for ALS and approved therapies only moderately slow the progression of the disease.

About ALS Finding a Cure^®

ALS Finding a Cure^® is dedicated to being a game changer in discovering a cure for this fatal disease. Founded in 2014 by noted philanthropist and Conair Founder and Chairman, Leandro P. Rizzuto, as a tribute to Christie Rizzuto, his daughter-in-law who was diagnosed with ALS in 2009 at the age of 41, and under the leadership of Denis Rizzuto, Peter N. Foss, and a team of renowned ALS researchers, ALS Finding a Cure® is focused on identifying the gaps in the scientific understanding of ALS that are preventing the development of a cure. The organization, a program of The Leandro P. Rizzuto Foundation, collaborates with a wide range of companies, ALS organizations, other disease research organizations, and ALS patients and families to ensure research efforts are non-duplicative, synergistic, and focused on the ultimate goal: finding a cure.

About The ALS Association

The ALS Association is the largest philanthropic funder of ALS research in the world. The Association funds global research collaborations, assists people with ALS and their families through its nationwide network of care and certified clinical care centers, and advocates for better public policies for people with ALS. The ALS Association is working to make ALS a livable disease while urgently searching for new treatments and a cure. For more information about The ALS Association, visit our website at www.als.org.

Bridging Voice is a non-profit that provides communication technology support to people with ALS at all stages. To date our team has supported over 1,500 pALS in 49 states and 12 countries. We strive to provide innovative solutions, continued communication, improved quality of life, and hope to the larger ALS community.

Funding from ALSFAC will enable Bridging Voice to expand programs that give people with ALS (pALS) the ability to continue to communicate with their family, friends and caregivers. Bridging Voice will provide the education, training and technical support to ensure pALS are always able to communicate both in-person and online. In addition, Bridging Voice will develop new innovations and customizations to improve communication for pALS and provide these innovations to other practitioners free of charge through open source development as well as an ongoing training series for practitioners. These programs will improve communication and support for people with ALS as well as creating an ecosystem that fosters collaboration and strengthens the ALS community across the country and around the world.

Matt’s Place Foundation: “ Hope & Housing ALS Renovation Series” Matt’s Place Foundation(MPF) is a 501(c)(3) charitable organization run 100% by volunteers to assist pALS (People with ALS) and their families, as they navigate learning to live with this disease. Its ultimate intention is to provide hope, housing, and assistance to families dealing with ALS. MPF helps families diagnosed with Amyotrophic Lateral Sclerosis (ALS) by providing grants and support with some of the more expensive costs that are not covered through insurance, such as accessible exterior ramps, accessible bathroom remodeling costs, and rent/mortgage assistance. The foundation has built two award-winning “Ultimate ALS Homes” designed specifically for pALS, their families, and caregivers to live, free of charge, for the duration of their illness. The “Ultimate ALS Homes” are single family homes with full voice/eye gaze-controlled home automation and environmental controls, and accessibility. Effective accessibility remodels/homes for pALS allow for dignity and independence, while also relieving some of the caregiver and financial burden. The generous funding from ALSFAC We Care will help Matt’s Place Foundation (MPF) create, market, and distribute a nationally recognized, online video series titled “Hope & Housing” designed to help someone newly diagnosed with ALS (pALS) and their caregiver (cALS) quickly equip themselves to be able to remain in their home with their family for the duration of their lives. MPF has learned many valuable lessons and questions to ask when remodeling homes with pALS and cALS in mind. Often after an ALS diagnosis, families are unaware of the remodeling and accessibility needs and requirements that are necessary to safely care for and assist someone with ALS in their own home. Simply updating a home per ADA requirements is not enough to safely care for someone with ALS, and to help them live with independence and dignity. Researching and anticipating needs can be overwhelming and tends to all fall on the caregiver. MPF’s goal is to help relieve some of the burden that falls on caregivers’ shoulders, by demonstrating how to use equipment, understanding what would make sense for their situation, and how to communicate needs with local contractors to ensure everything is installed and operating effectively, while preserving precious resources.

ALS Ride For Life (ALSRFL) is a non-profit located in Stony Brook, New York. ALSRFL was founded 26 years ago by Chris Pendergast. When Chris was diagnosed with ALS he decided he wanted to be part of the solution and ALSRFL was founded.

Chris quickly realized patients needed a wheel-chair accessible van to get to much needed doctor appointments and to attend family events. He started lending out his personal van. As the demand grow, ALSRFL started its Mobility Matters Program. This program is the only one of its kind serving Long Island the NYC Metropolitan area.

To date ALSRFL has raised over $10 million dollars used to support research and many other patient service programs both locally and nationally.

Pease visit alsrideforlife.org to learn more.

Shockingly, more than 150 years after the disease was first defined, there are currently no universally accepted diagnostic approaches for ALS. In order to receive an ALS diagnosis patients must first undergo a battery of tests designed to rule out other diagnoses. This is highly problematic because it can take a year for an ALS patient to receive the correct diagnosis (and sometimes even longer). While these individuals are searching for a name for their affliction, they are frequently bounced to multiple doctors, can receive unnecessary (and expensive) surgical procedures and medications, and sadly can become ineligible for ALS clinical trials. The ALS field urgently needs to close this gap!

Given this critical need in the field, ALS Finding a Cure® and the ALS Association are pleased to announce that they have joined forces to issue an open international call for proposals designed to encourage the identification of early diagnostic markers of ALS. We are particularly interested in encouraging diverse and multidisciplinary research teams to attack this problem.

Examples of approaches that might be supported by this request for proposals include, but are not limited to, the following:

Grants will support 3-year proposals with a maximum total budget of $500,000 USD total (inclusive of both direct and indirect costs).

Deadlines:

Proposals due: March 1, 2023 5pm US ET

Anticipated Award Decision: April 30, 2023

Anticipated Earliest Start Date: June 15, 2023

Submit to: https://app.box.com/f/6332c1c7e65b46969236884f37cf7535

Application Process

1. Please provide a cover letter addressed to ALS Finding a Cure and the Leandro P. Rizzuto Foundation including:

• Proposal Title
• Total costs (15% overhead cap)
• Number of milestones and related costs (to equal amount above)
• List of all investigators and institutions
• Name and contact information for person(s) responsible for contracts
• Address for mailing of payments

2. Provide a study plan including:

• A brief abstract suitable for media release to the lay public if the application is successful
• Project Plan, Background, and Timeline (max. 5 pages) including:
• Study background and rationale/significance
• Study objectives/specific aims
• Supporting/preliminary data;
• Experimental design/research plan;
• Detailed itemized budget and budget justification
• Description of study milestones, including the costs associated and timeline of specific deliverables
• Any research funding from other funding sources that relates to the proposed work

3. Signed and dated investigator CVs 

4. Financial Disclosure Form: use either NIH form https://ethics.od.nih.gov/forms450 ), or institutional form. 

Please submit questions to info@alsfac.org