Leading the worldwide fight to treat and cure
Tay-Sachs, Canavan, GM1 and Sandhoff diseases

Adeno-Associated Virus (AAV) Delivery Routes

1) Intraparenchymal Delivery of AAV
Intraparenchymal, also referred to as intracranial, refers to directly injecting AAV vectors in to the brain parenchyma, or brain tissue. This strategy allows targeting of specific brain regions, such as highly interconnected white matter tracts or specific brain nuclei, and occurs within the blood-brain barrier. The number and location of injections, the vector serotype, and properties of the enzyme will determine the spread of the treatment throughout the central nervous system (CNS, brain and spinal cord). Due to directly injecting brain tissue there can be unfortunate effects such as hemorrhage. This was the strategy used in an early Canavan trial in which AAV2 was delivery in six cranial burr holes (https://www.ncbi.nlm.nih.gov/pubmed/16532510).

2) Intra-CSF Delivery of AAV
Delivery of AAV into the cerebrospinal fluid (CSF) can be performed in the brain or the spinal cord. CSF delivery avoids directly injecting brain tissue yet still occurs within the blood-brain barrier.

Intracerebroventricular (ICV)- ICV refers to delivery of AAV into ventricles, or large cavities in the brain that hold CSF. The largest and most common ventricles to target are the lateral ventricles. Each cerebral hemisphere, left and right, contains a lateral ventricle.

Intra-cisterna magna- also referred to intrathecal at the cerebellomedullary cistern, occurs at the top of the spinal cord, or the space between the bottom most part of the brain, the cerebellum, and the top of the spinal cord.

Intrathecal (IT)- also referred to as lumbar intrathecal, occurs at the bottom of the spinal cord. Lumbar intrathecal delivery is considered the least risky of the CSF delivery routes; however, the AAV vector has the furthest to travel to reach the brain. This is the strategy being utilized in the Batten disease (CLN6) clinical trial (https://clinicaltrials.gov/ct2/show/NCT02725580).

3) Intramuscular Delivery of AAV
AAV can be directly injected in to muscle for diseases that primarily affect the heart and/or skeletal muscle. This strategy is being utilized in the clinical trial for the lysosomal storage disease Pompe disease (https://clinicaltrials.gov/ct2/show/NCT02240407).

4) Systemic/Intravascular Delivery of AAV
Systemic or intravascular is delivery of AAV vectors directly to the blood system. Certain serotypes of AAV, such as AAVrh8, AAV9 and AAVrh10, have the ability to cross the blood-brain barrier. Those serotypes can be used for systemic/intravascular delivery to target systemic disease as well as the central nervous system (CNS, brain and spinal cord). The procedure itself is non-invasive; however, a larger volume of AAV vector is required and the amount of vector that reaches the CNS is typically less than targeting the CNS directly. High levels of vector and enzyme can also be found in specific systemic tissues, such as the liver, due to delivery in to blood circulation.

Intravenous (IV)- most commonly systemic/intravascular delivery of AAV vectors is done through a venous catheter into a limb vein. This is the strategy being utilized for the MPSIIIA, or Sanfilippo syndrome, clinical trial (https://clinicaltrials.gov/ct2/show/NCT02716246).

Intra-arterial (IA)- there are ongoing studies in animal models, although no human clinical trials, evaluating delivery of AAV in to arteries instead of veins. The most common arteries being investigated are the carotid and femoral arteries.


Response to Expanded Access Thread on Facebook

NTSAD recognizes the URGENCY families have and the frustration that we aren’t yet in a clinical trial for our diseases, in this instance, Canavan.  Here are a few things we want to clarify about what happened (as far as we know), our limited role, and where we hope to go from here.

Expanded access:  This is a complicated, always evolving, topic. Expanded access is now a preferred term for compassionate use and is a single-patient process. More than one patient can use an investigational drug via expanded access, but each patient/physician group must apply to the FDA. It is not a clinical trial. There are no specific numbers of patients associated with it. There are often limits to the amount of drug available, which is one of the limiting factors of expanded use.  Note that there are risks to expanded access use for the researcher/company and the patient population. A serious complication in using a drug through expanded access could delay future trials or shut down the entire research program.

This FDA link explains the terminology about how Expanded Access works.  It does not use an FDA-approved treatment.  The web site states, “Wherever possible, use of an investigational medical product by a patient as part of a clinical trial is preferable because clinical trials can generate data that may lead to the approval of products and, consequently, to wider availability.”  As a patient advocacy organization, NTSAD’s goal is to partner with families, researchers, and companies to pursue a clinical trial so that there will be wider availability of any treatment. 

Yes, in this case, it appears that an agreement was worked out between a researcher and a clinician and their respective institutions along with the FDA to treat a single child by expanded access.  The institutions and family worked out this arrangement without NTSAD’s involvement. Yes, this family raised the money needed for this expanded access treatment.  They understandably desired privacy, which we respect.  In learning of this child’s treatment, our role is to follow-up with investigators and institutions to see how we can bring this treatment to a sponsored clinical trial (in which all costs are paid for by the sponsor), and therefore to families at large. That is happening now.

NTSAD’s role in funding Canavan gene therapy / all research:  NTSAD funds research in a competitive process with scientific reviews.  We invite researchers to our conference to share updates about the research.  Dr. Gao received a $40,000 NTSAD Research Initiative grant in 2011.  NTSAD has reported on the results of that grant and have periodically shared updates based on publications about the gene therapy.  Our role is not to spend funds for one specific patient nor to encourage treatment for one specific patient, but to encourage progress (which requires a clinical trial) for all patients. Both Dr. Gao and Dr. Gessler have attended many conferences, shared data in the research sessions, and talked at length with families about their ongoing work.

NTSAD’s role in making information available to the patient community: NTSAD’s role is to be a trusted partner for families, scientists, clinicians, and companies so that we can help advance research to treatments.  The ways we help advance research are funding, learning about the disease through direct contact with families, sharing knowledge about the disease, developing ways to gather information about our diseases, and connecting with our network.  Transparency is not the same as sharing everything we know as soon as we know it. NTSAD is sometimes asked to sign confidentiality agreements with companies or researchers.  If we want anyone to work with us, we must respect these arrangements.

If you have further questions or need further clarification, we hope you reach out. Especially if you see something posted that may not be accurate or is confusing. We are here to help decipher the news that is shared related to the diseases that impact our community, and we have the researchers and clinicians who are experts in their field who advise us on a daily basis.

Feel free to contact Sue Kahn, Executive Director This email address is being protected from spambots. You need JavaScript enabled to view it. or Diana Pangonis, Director of Family Services This email address is being protected from spambots. You need JavaScript enabled to view it..

Issues Today

From our friends at EveryLife Foundation (December 20, 2017)

Capitol Hill Updates

The House and Senate have passed a conferenced version of the Tax Cuts and Jobs Act, which makes cuts to the Orphan Drug Tax Credit (ODTC), a key provision of the Orphan Drug Act which incentivizes rare disease treatment research by lowering development costs for manufacturers. This version of the bill would reduce the tax credit’s value from 50% to 25%. The bill also makes changes to the medical expense deduction, which is currently utilized by approximately eight million Americans who have medical expenses that exceed 10% of their adjusted gross income. This deduction can now be taken for medical expenses exceeding 7.5% of income. Click here to read about the final tax bill.

The final tax reform legislation repeals the Affordable Care Act’s individual mandate, which requires individuals to enroll in an insurance plan or face a financial penalty. Earlier this year, the Congressional Budget Office (CBO) estimated that repealing the mandate would raise the number of uninsured individuals to 13 million by 2027. Click here to read about what repealing the mandate could mean for insurers.

The Children’s Health Insurance Program (CHIP) expired on September 30 but is still awaiting Senate reauthorization. It provides affordable, comprehensive health insurance for children in families with too much income to qualify for Medicaid, but struggle to afford private insurance. A Continuing Resolution passed earlier this month extended current spending levels for two weeks in order to prevent government shutdown. States like Connecticut are already planning to close their healthcare program for low and middle-income children by January 31 if Congress fails to extend federal funding. Click here for more information.

Earlier this month, the Food and Drug Administration (FDA) released draft guidance entitled, “Pediatric Rare Diseases —A Collaborative Approach for Drug Development Using Gaucher Disease as a Model Guidance for Industry.” The guidance covers the use of age-specific endpoints, extrapolation from adult studies to demonstrate treatment efficacy, and strategies for designing multi-arm clinical trials. Click here to read more.

In response to public feedback on Patient Participation in Medical Product Discussions of the Food and Drug Administration Safety and Innovation Act (FDASIA), the FDA created the Patient Engagement Collaborative (PEC). The PEC will focus on how to incorporate meaningful patient engagement in medical product development discussions. The Agency is seeking participants from the patient community, caregivers and individuals who represent patient groups. Click here for more information


Community Action Alerts & Policy Resources

First Focus is encouraging patient advocates to sign-on to a letter asking Congress to extend CHIP funding. They note that the program is critical for the 8.9 million children that depend on it. Click here to read the letter and sign-on.

Research!America is asking advocates to write to their Members of Congress urging them to oppose legislation that would provide funding for the Department of Defense while holding non-defense discretionary spending static. This would impact agencies like the National Institutes of Health (NIH) and FDA. Click here to take action.

The Epilepsy Foundation is asking patient advocates to write to their legislators to encourage them to oppose the Americans with Disabilities Act (ADA) Education and Reform Act of 2017 (HR 620). According to the Foundation, the bill would weaken protections for people living with disabilities by making it easier for businesses to avoid complying with the accessibility requirements of the ADA. Click here to take action.

The EveryLife Foundation for Rare Diseases is asking individuals to contact their Members of Congress in support of the OPEN ACT (Orphan Product Extensions Now, Accelerating Cures and Treatments; HR 1223/ S1509) which has the potential to double the number of treatments approved by the Food and Drug Administration (FDA) for rare diseases. For more information and to take action, click here.


Community Events

On January 25, the NIH will hold a symposium entitled, “Global Perspectives on Standards and Common Data Elements Used in Patients Data and Biospecimens Collection.” Click here for more information.

On February 25 to March 1, RDLA will host Rare Disease Week on Capitol Hill. Events include a rare disease documentary screening and cocktail reception, Legislative Conference, Lobby Day, Rare Disease Congressional Caucus briefing, Rare Artist reception, and Rare Disease Day at the NIH. Click here for more information, including the schedule of events.  Registration will open on January 3, 2018.

On March 1, as part of Rare Disease Week on Capitol Hill, the NIH will host Rare Disease Day at NIH. This event aims to raise awareness about rare diseases, the people they affect and NIH research collaborations to advance new treatments. Click here for more information.

On March 8, the FDA will convene a public workshop on “Safety Assessment for Investigational New Drug Safety Reporting.” Click here for more information

On March 19 to 21, World Congress will host the 6th annual Patient Advocacy Summit. Industry leaders, patient advocates and policy makers join to tackle the complexities of patient advocacy and the healthcare market. Click here for more information.

NTSAD Care Tips Series

The goal of this series is to document and capture information that relates to the family experience in all its forms (caring for a child, grief, living with the adult onset forms) and the symptom and care management involved. These videos allow families, supporters and healthcare professionals worldwide to have access to information that may not be readily available to them in their area. An imperative goal of this series is to relieve the isolation brought on by these rare diseases.

To translate these videos:

Settings > Select Subtitles: English > Go back to Subtitles: Auto-translate > Select language

The translation will appear as subtitles albeit roughly translated.

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