The Muscular Dystrophy Association has awarded a $278,850 grant to the ALS Therapy Development Institute (ALS TDI) in Cambridge, Mass., to support testing of a mouse version of a compound called CTLA4-FC in the SOD1 research mouse model of amyotrophic lateral sclerosis (ALS).
"MDA is excited to support the study of CTLA4-FC as a potential ALS therapy," said Jane Larkindale, director of translational research at MDA. "The existence of compounds such as abatacept, already on the market today, could favorably impact the speed of clinical development should the preclinical study show promise."
The ALS TDI grant comes through MDA Venture Philanthropy (MVP), MDA’s translational research program, which aims to move promising drugs from the laboratory to clinical trials as quickly as possible.
A growing body of evidence suggests that malfunction of the immune system is at least part of the ALS disease process, and previous studies conducted at ALS TDI have shown that blocking activation of a part of the immune system called the costimulatory pathway slows disease progression and improves survival in SOD1 ALS mice.
In humans, CTLA4-FC blocks activation of the costimulatory pathway by targeting a signaling protein called CD86.
Now, ALS TDI scientists are testing whether mouse CTLA4-FC effectively blocks CD86 signaling and leads to slower disease progression and improved survival in the ALS mice.
Human CTLA4-FC (abatacept) is a human fusion protein— a type of molecule that is created by joining two or more genes that normally would each carry instructions for different proteins. When cellular machinery reads the instructions carried by the new gene construct, it produces a sort of "hybrid" molecule that exhibits functional properties derived from each of the original proteins.
When used to treat rheumatoid arthritis, abatacept is administered by intravenous infusion or subcutaneous (under the skin) injection.
Abatacept differs from mouse CTLA4-FC in very important ways, so researchers caution against drawing too close a parallel between the two compounds at this early stage of ALS TDI's investigation.
Although human CTLA4-FC and mouse CTLA4-FC hit the same target, they are not the same compound. In addition, it's not known what effects CTLA4-FC has in ALS, either in the human form of the disease or in the SOD1 mouse.
Therefore, although abatacept is available by prescription for treatment of arthritis, it’s strongly recommended that individuals with ALS not seek an off-label prescription for the drug. ("Off label" refers to a physician’s use of a drug or therapy to treat conditions other than the ones for which it received FDA approval.)
"We don’t know yet whether the drug is effective in mice, much less in people with ALS, and we also don’t know whether it is even safe in those with ALS," cautioned Valerie Cwik, MDA Executive Vice President-Research and Medical Director. "MDA does not recommend taking abatacept for the treatment of any condition other than that for which it has FDA approval."
However, because there already are drugs on the market that block CD86, including abatacept, successful studies in the SOD1 mouse could lead to rapid development and FDA approval of a drug targeting CD86 as an ALS therapy.
MDA and ALS TDI are partners in the largest ALS drug discovery project in history, aimed at identifying biological components and pathways in ALS and finding drugs that target them.
"ALS TDI is thrilled to be able to work with MDA Venture Philanthropy on this project," said Steve Perrin, CEO & CSO of ALS TDI. "We are excited to screen the mouse version of CTLA4-FC in the SOD1 ALS research mouse model. We are also excited that this continues our joint-collaboration with MDA to discover and develop effective treatments for ALS."