Potential Therapies for Neuromuscular Disorders

Question 1

Where do therapies for neuromuscular disorders
stand currently?

Answer 1

1. Immense research efforts and $$$ in quest for therapies.
2. Most CLINICAL TREATMENTS to date include: NOT DUE TO GENE INFOMATION OR IS NOT CURES …alleviate symptoms
   - 1. steroids
   - 2. physiotherapy
   - 3. orthopaedic input
   - 4. ventilatory support
   - 5. cardiac surveillance
3. however CLINICAL TRIALS ARE OCCURRING and therefore still hope

Question 2

CHALLENGES OF DESIGNING A THERAPY; 1

Answer 2

CHALLENGE =muscle makes up to 40% of a person’s body
- multiple opportunities to get harmed/ disease occur

2. CHALLENGE: DELIVERY OF A THERAPY
   - INJECTION into MUSCLE will TRANSDUCE CELLS only within a COUPLE OF CENTIMETRES OF THE INJECTION SITE
3. CHALLENGE: MULTIPLE INJECTIONS required
   - INJECTIONS FOR THE HEART OR DIAPHRAGM MUSCLE = 100s needed
   - NOT REALISTIC

Question 3

challenge 2: for designing a therapy

Answer 3

1. Any therapy direct injections into muscle are probably doome to failure unless THE INJECTION CAN PROVIDE A ‘ONE-OFF PERMANENT CURE’

• ideally would need LONG TERM DELIVERY OF MISSING GENE or PERSISTENT GENE CORRECTION
• this currently ules out most approaches which have been advocated.

therefore SYSTEMIC DELIVERY - AN INJECTION STRAIGHT INTO ATERY, OR A TABLET THAT DELIVERS A DRUG TO ALL OF THE BODY
- ideal approach

Question 4

CHALLENGE OF DESIGNING A THERAPY = NO. 3

Answer 4

1. MUSCLE diseases can be very SEVERE and thus MANY AFFECTED PEOPLE are BORN WITH THE DISEASE
   - TREATMENT NEEDS TO BEGIN VERY EARLY (POSSIBLE IN UTERO)

…. many of the defective genes are VERY LARGE (eg. larger than SIZE LIMIT FOR VIRAL VECTORS).

…there are many different genes an many different mutations, thus there likely to NOT be a “one-size fits all”

Question 5

Moving forward = 4

Answer 5

1. Maybe expectation is too high if we expect any SINGLE THERAPEUTIC APPROACH WILL BE AN ULTIMATE PANACEA
2. even a delay in disease onset or slowing progress may be significant to patients and families.

3, many approaches under investigation attack the problems from various directions

4. this raises the possibility for combinatorial therapies, with each contributing an improvement which could be additive.

Question 6

Strategies for rational design of a therapy…WHAT WE NEED TO START WITH

Answer 6

1. knowledge of the disease causing gene mutation
2. understanding of the PATHWAY, PATHOBIOLOGY, DISEASE MECHANISM – whether the DISEASE IS DOMINANT OR RECESSIVE IS IMPORTANT
3. an appropriate model for SCREENING/TESTING PUTATIVE THERAPIES - in vitro or in vivo
4. knowledge of the different therapeutic strategies, their benefit and limitations.