Massachusetts General Hospital (MGH)

Genome Editing for ALSP.

What is ALSP? ALSP is a devastating brain disorder that affects a person’s ability to think, make decisions, be independent, communicate, interact with others, move, and/or control their bowel and bladder. Most affected patients have a mutation in the CSF1R gene. This gene is necessary for the survival and function of microglia and monocyte cells. Microglia live in the brain and are constantly at work to maintain normal brain function. Monocytes usually live in the blood but can travel to the brain and turn into microglia-like cells. CSF1R mutations that disrupt these cell types cause the symptoms associated with ALSP.

What is genome editing? Genome editing is a potential therapy for ALSP that corrects the underlying disease-causing CSF1R gene mutation in the DNA. For most ALSP patients, the mutation is a typo in one of the letters of the DNA, which changes the meaning of the DNA. To draw a parallel with the English language, when H-O-T is misspelled as H-A-T, it completely changes the meaning of the word. Like human proofreaders that catch and correct misspellings, genome editors find the misspelled letter in the DNA and change it back to the correct letter to restore normal CSF1R function. So far, more than 300 unique mutations in CSF1R have been identified. Each genome editing therapy is personalized to correct one specific CSF1R mutation.

What research is being done in genome editing for ALSP patients? Genome editing is a promising treatment for ALSP patients that is currently in preclinical development at MGH and UCSF. This means scientists at both institutions are actively working together to show the effectiveness and safety of genome editing for ALSP in the laboratory setting. This work must be completed before clinical trials for genome editing therapies can begin. Research is currently focused on delivery of genome editing therapies to hematopoietic stem cells (HSCs), which live in the bone marrow. Bone marrow transplantation, which replaces an ALSP patient’s bone marrow with bone marrow from a healthy donor, can slow or halt disease progression. However, not all patients have a matching donor. Genome editing corrects the disease-causing mutation in the HSCs from ALSP patients, which allows patients to be their own bone marrow donor and eliminates the donor search.

How can patients contribute to ALSP genome editing research? Laboratory-based tests for effectiveness and safety of genome editing cannot be done without cells donated by ALSP patients. Since each genome editing therapy is personalized to correct one specific CSF1R mutation, we need donations from patients with different CSF1R mutations. We also need to test whether one genome editing therapy is effective and safe for different patients who share the same mutation. To do these tests, we are collecting blood cells through a routine blood draw and skin cells through a skin biopsy.

What does a clinic visit include?

1. Medical appointment: The primary purpose of the clinic visit is to establish (or continue) clinical care with a clinician who is an expert in treating ALSP. Thus, the visit will start with a routine new MASSACHUSETTS GENERAL HOSPITAL HARVARD MEDICAL SCHOOL patient (or established patient) visit during which the patient’s clinical and medical history will be recorded in detail, and the patient will undergo a detailed neurologic exam. Prior brain imaging will be reviewed with the patient. As with any other doctor’s visit, changes in medications may be recommended depending on each patient’s situation and symptoms. Blood may also be drawn for clinical labs that are not related to research.

2. Research: The clinical research team will explain the process and purpose of giving blood and skin samples in detail. Clinicians will be available to answer any questions that come up. If patients agree to participate in research, they (or their healthcare proxy) will be asked to sign a consent form.

a. Blood collection: Blood donation for research will be drawn with clinical labs to minimize needle sticks.

b. Skin biopsy: The healthcare provider performing the skin biopsy will explain the procedure in detail and obtain the skin biopsy if the patient agrees to undergo the procedure.

3. Insurance coverage: Research-related blood donation and skin biopsies will be covered by research funding and will not be billed to insurance. However, routine clinical care that is not research-related will be billed to the patient’s insurance. Our clinic coordinators can assist patients with obtaining insurance approval prior to the appointment.

How can patients prepare for the clinic visit?

1. Please ensure that all existing medical records are sent to the doctor’s office before the appointment, including genetic testing results, doctor’s notes, neuropsychiatric test reports, and laboratory results.

2. Please ensure that all imaging, including brain MRI and head CT scans have been received by the doctor’s office. It is very important that the doctor’s office receives the actual images, not just the radiology report(s) associated with the imaging. If the doctor’s office is unable to obtain the images electronically, patients may need to get a physical copy of the imaging on a CD and bring it to their clinic visit. Office staff will upload the images from the CD into the patient’s medical chart.

3. If possible, please have a detailed record of family history for any neurologic or psychiatric disorders. Because ALSP can be inherited, and it is often misdiagnosed, you will be asked about family history of multiple sclerosis, dementia (Alzheimer disease, frontotemporal dementia, corticobasal syndrome, etc.), movement disorders (Parkinson disease, progressive supranuclear palsy, tremor, etc.), psychiatric disorders (depression, anxiety, psychosis, bipolar disorder, schizophrenia, etc.), stroke, and hydrocephalus.

How can I make an appointment and have my travel covered? If you would like to set up an appointment at MGH, please contact Dr. Yedda Li at yli@mgh.harvard.edu. Please include “ALSP” in the subject line. For those in financial need, funding for travel expenses is available for both patients and caregivers. No proof of need is required.

If you are interested in learning more, please contact:

Dr. Yedda Li - Principal Investigator (yli@mgh.harvard.edu)